Prognostic value of neutrophil-to-lymphocyte ratio dynamics in patients with septic acute kidney injury: a cohort study.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a prognostic marker for various diseases, but whether NLR dynamics (ΔNLR) is related to mortality and disease severity in patients with septic acute kidney injury (AKI) has not been determined. METHODS: Between August 2013 and August 2021, septic AKI patients at our center were retrospectively enrolled. ΔNLR was defined as the difference between the NLR at septic AKI diagnosis and at hospital admission. The relationship between the ΔNLR and mortality was evaluated by Kaplan-Meier curves, Cox proportional hazards, and cubic spline analyses. The prediction values were compared by area under the receiver-operating characteristic curve (AUROC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses. RESULTS: Of the 413 participants, the mean age was 63 ± 17 years, and 134 were female (32.4%). According to the median value, patients in the high-ΔNLR group had significantly greater 90-d mortality (74.4% vs. 46.6%, p < 0.001). After adjustment for potential confounders, high ΔNLR remained an independent predictor of 90-d mortality (HR = 2.80; 95% CI = 1.74-4.49, p < 0.001). Furthermore, ΔNLR had the highest AUROC for 90-d mortality (0.685) among the various biomarkers and exhibited an improved NRI (0.314) and IDI (0.027) when incorporated with PCT and CRP. For secondary outcomes, patients with high ΔNLR had increased risk of 30-d mortality (p = 0.004), need for renal replacement therapy (p = 0.011), and developing stage-3 AKI (p = 0.040) according to the adjusted models. CONCLUSIONS: High ΔNLR is independently associated with increased risk of patient mortality and adverse outcomes. ΔNLR might be utilized to facilitate risk stratification and optimize septic AKI management.

The role and mechanism of macrophage autophagy in the experimental model of chronic obstructive pulmonary disease.

INTRODUCTION: Macrophages play an important role in chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) impairs autophagy in alveolar macrophages from COPD patients, and autophagic impairment leads to reduced clearance of protein aggregates, dysfunctional mitochondria, and defective bacterial delivery to lysosomes. However, the exact function of lung macrophage autophagy in the pathogenesis of CS-induced COPD remains largely unknown. METHODS: Western blot detected the expression of autophagy-related proteins induced by CSE. The model of COPD mice was established by CS exposure combined with CSE intraperitoneal injection. Double immunofluorescence was used to measure the CD206+LC3B+ cells. The morphological changes and effects on lung function were observed. Masson staining detected the changes in collagen fibers in lung tissue. The expression levels of E-cadherinb and N-cadherinb were detected by immunohistochemistry. Western blot detected the expression of ATP6V1E1 in lung tissue. RESULTS: At 24 hours of exposure to CSE, the expression levels of LC3B (microtubule-associated protein 1A/1B-light chain 3B) and P62 (nucleoporin 62) were highest at 1% CSE and AGT5 (nucleoporin 62) at 2.5% CSE; at 48 hours, the expression levels of LC3B, P62 and AGT5 were highest at 2.5% CSE, and as the intervention time increased.CD206+LC3B+ cells were significantly higher in the COPD group. Enhanced macrophage autophagy may promote emphysema formation and aggravate lung function damage. The expression of E-cadherinb in lung tissue of the COPD group was decreased, and N-cadherinb expression was increased; the expression of E-cadherinb was increased, and N-cadherinb expression was decreased in ATG5myeΔ COPD mice. The expression of ATP6V1E1 in the lung tissue was increased in the COPD group; ATP6V1E1 expression was decreased in the lung tissues of ATG5myeΔ COPD mice. CONCLUSIONS: CSE enhanced macrophage autophagy, leads to increased lung function impairment and collagenous fiber in lung tissue, as well as promotes epithelial-mesenchymal transition, and eventually leads to small airway remodeling, which may be achieved through the ATG5/ATP6V1E1 pathway.

Exploring the diagnostic value of ultrasound radiomics for neonatal respiratory distress syndrome.

BACKGROUND: Neonatal respiratory distress syndrome (NRDS) is a prevalent cause of respiratory failure and death among newborns, and prompt diagnosis is imperative. Historically, diagnosis of NRDS relied mostly on typical clinical manifestations, chest X-rays, and CT scans. However, recently, ultrasound has emerged as a valuable and preferred tool for aiding NRDS diagnosis. Nevertheless, evaluating lung ultrasound imagery necessitates rigorous training and may be subject to operator-dependent bias, limiting its widespread use. As a result, it is essential to investigate a new, reliable, and operator-independent diagnostic approach that does not require subjective factors or operator expertise. This article aims to explore the diagnostic potential of ultrasound-based radiomics in differentiating NRDS from other non-NRDS lung disease. METHODS: A total of 150 neonatal lung disease cases were consecutively collected from the department of neonatal intensive care unit of the Quanzhou Maternity and Children's Hospital, Fujian Province, from September 2021 to October 2022. Of these patients, 60 were diagnosed with NRDS, whereas 30 were diagnosed with neonatal pneumonia, meconium aspiration syndrome (MAS), and transient tachypnea (TTN). Two ultrasound images with characteristic manifestations of each lung disease were acquired and divided into training (n = 120) and validation cohorts (n = 30) based on the examination date using an 8:2 ratio. The imaging texture features were extracted using PyRadiomics and, after the screening, machine learning models such as random forest (RF), logistic regression (LR), K-nearest neighbors (KNN), support vector machine (SVM), and multilayer perceptron (MLP) were developed to construct an imaging-based diagnostic model. The diagnostic efficacy of each model was analyzed. Lastly, we randomly selected 282 lung ultrasound images and evaluated the diagnostic efficacy disparities between the optimal model and doctors across differing levels of expertise. RESULTS: Twenty-two imaging-based features with the highest weights were selected to construct a predictive model for neonatal respiratory distress syndrome. All models exhibited favorable diagnostic performances. Analysis of the Youden index demonstrated that the RF model had the highest score in both the training (0.99) and validation (0.90) cohorts. Additionally, the calibration curve indicated that the RF model had the best calibration (P = 0.98). When compared to the diagnostic performance of experienced and junior physicians, the RF model had an area under the curve (AUC) of 0.99; however, the values for experienced and junior physicians were 0.98 and 0.85, respectively. The difference in diagnostic efficacy between the RF model and experienced physicians was not statistically significant (P = 0.24), whereas that between the RF model and junior physicians was statistically significant (P < 0.0001). CONCLUSION: The RF model exhibited excellent diagnostic performance in the analysis of texture features based on ultrasound radiomics for diagnosing NRDS.

Special Staining and Protein Expression of VEGF/EGFR and P53/NF-κB in Cryptorchid Tissue of Erhualian Pigs.

Erhualian pigs exhibit one of the highest reproductive rates globally, and cryptorchidism is a crucial factor affecting reproductive abilities of boars. This investigation focused on cryptorchid tissues from Erhualian pigs, where the histological structure of cryptorchidism was observed using specialized staining. In addition, protein expression of P53/NF-κB in cryptorchid tissues was assessed using Western blot and immunohistochemistry. In comparison to normal Erhualian testes, Masson's trichrome staining indicated a reduction in collagen fibers in the connective tissue and around the basal membrane of the seminiferous tubules in cryptorchid testes. Moreover, collagen fiber distribution was observed to be disordered. Verhoeff Van Gieson (EVG) and argyrophilic staining demonstrated brownish-black granular nucleoli organized regions in mesenchymal cells and germ cells. When compared to normal testicles, the convoluted seminiferous tubules of cryptorchids exhibited a significantly reduced number and diameter (p < 0.01). Notably, VEGF/EGFR and P53/NF-κB expression in cryptorchidism significantly differed from that in normal testes. In particular, the expression of VEGF and P53 in cryptorchid tissues was significantly higher than that in normal testes tissues, whereas the expression of EGFR in cryptorchid tissues was significantly lower than that in normal testes tissues (all p < 0.01). NF-κB expressed no difference in both conditions. The expressions of VEGF and NF-κB were observed in the cytoplasm of testicular Leydig cells and spermatogenic cells, but they were weak in the nucleus. EGFR and P53 were more positively expressed in the cytoplasm of these cells, with no positive expression in the nucleus. Conclusion: There were changes in the tissue morphology and structure of the cryptorchid testis, coupled with abnormally high expression of VEGF and P53 proteins in Erhualian pigs. We speculate that this may be an important limiting factor to fecundity during cryptorchidism.

Stents migration into right atrium from severely calcified superior vena cava in a hemodialysis patient.

Vascular calcification is common among hemodialysis patients. In this report, we presented a case of superior vena cava (SVC) stent migration during endovascular angioplasty in a 50-year-old female hemodialysis patient with severe SVC calcification. The stent migration was refractory to the deployment of a second anchor stent, which shortly resulted in pericardium tamponade and was successfully rescued by emergent thoracotomy. The potential role of vascular calcification as a risk factor to stent migration was discussed. Patients with severe vascular calcification receiving endovascular angioplasty might need a careful risk screening for stent migration.

Serum total protein-to-albumin ratio predicts risk of death in septic acute kidney injury patients: A cohort study.

OBJECTIVE: Sepsis is the leading cause of acute kidney injury (AKI). Increasing evidence shows that serum total protein-to-albumin ratio (TAR) could serve as an inflammation- and nutrition-based prognostic marker in various diseases. The purpose of this study was to assess the prognostic value of TAR in predicting the clinical outcomes of septic AKI patients. METHODS: We retrospectively enrolled septic AKI patients between August 2015 and August 2022 at West China Hospital of Sichuan University. Patients admitted between August 2015 and August 2021 were defined as the original cohort. The primary outcomes were 30-day and 90-day all-cause mortality of septic AKI patients. The secondary outcomes were septic shock, transfer to the intensive care unit, mechanical ventilation, requirement for renal replacement therapy, and stage 3 AKI. The utility of TAR was further verified in a validation cohort of septic AKI patients admitted between September 2021 and August 2022. RESULTS: In the original cohort, a total of 309 eligible patients with a median age of 58 years were enrolled, of which 70.2 % were males. In multivariate Cox analysis, after adjustments for age, sex, and other confounding factors, higher TAR at admission was associated with an increased risk of 30-day and 90-day all-cause mortality in septic AKI patients (HR 1.91, 95 % CI 1.18-3.09, P = 0.008; HR 1.54, 95 % CI 1.01-2.34, P = 0.043, respectively). Subgroup analysis revealed no significant interactions in most strata. TAR at AKI diagnosis or discharge was not significantly related to 30-day (P = 0.120 and 0.153, respectively) or 90-day mortality (P = 0.147 and 0.124, respectively). We found no relationship between baseline TAR and septic shock, transfer to the intensive care unit, mechanical ventilation, requirement for renal replacement therapy, or stage 3 AKI (all P > 0.05). In the validation cohort of 81 septic AKI patients, TAR at admission remained a significant prognosticator for 30-day and 90-day mortality (HR 4.367, 95 % CI 1.20-15.87, P = 0.025; HR 4.237, 95 % CI 1.59-11.27, P = 0.004). CONCLUSIONS: TAR at admission is an independent risk factor for 30-day and 90-day mortality in septic AKI patients and could be used as a convenient and economic septic AKI prognostic indicator.

Sarcoidosis or Tuberculosis: Should Corticosteroids Be Used?

Sarcoidosis shows high similarity with tuberculosis in clinical manifestations and imaging features. It is rarely reported whether sarcoidosis patients with suspected latent tuberculosis can be treated safely with immunosuppressive therapy. We reported on a 54-year-old man who presented with enlarged lymph nodes persisting for decades, accompanied by renal impairment and refractory hypercalcemia. The patient was diagnosed with sarcoidosis and suspected latent tuberculosis (as suggested by a positive tuberculin test and tuberculosis interferon-gamma release assays) and received prednisone under follow-up. The patient showed significant amelioration in hypercalcemia and shrinkage of lymph nodes, without evidence of developing active tuberculosis. For sarcoidosis patients with suspected latent tuberculosis, immunosuppressive agents can be utilized safely based on close monitoring. Further efforts are required to reveal whether sarcoidosis and tuberculosis can trigger similar immune responses and what the clinical implications are.

Massive Hemorrhage Following Acupuncture Treatment in a Neurofibromatosis Type 1 Patient.

Neurofibromatosis type 1 (NF1) is a genetic disorder involving multiple organs. Vascular involvement is a rare complication among NF1 patients. We report a case of a 59-year-old female NF1 patient who presented with a massive hematoma over the scapular area after undergoing acupuncture treatment. Contrast-enhanced CT and MRI demonstrated a slightly hyperdense mass measuring 24.2 × 10.3 cm in size, and multiple enlarged and tortuous malformed vessels were seen arising from the left subclavian artery. Arterial embolization and subsequent surgical mass resection were successfully performed. This case indicates that minor injuries such as acupuncture-related ones could cause severe hemorrhage in patients with vascular malformation related to NF1. Endovascular angiography and embolization proved to be effective in localizing the culprit vessel and stopping active bleeding in our patient.

ATP protects anti-PD-1/radiation-induced cardiac dysfunction by inhibiting anti-PD-1 exacerbated cardiomyocyte apoptosis, and improving autophagic flux.

The synergy between radiotherapy and immunotherapy in treating thoracic cancers presents a potent therapeutic advantage, yet it also carries potential risks. The extent and nature of cumulative cardiac toxicity remain uncertain, prompting the need to discern its mechanisms and devise effective mitigation strategies. Radiation alone or in combination with an anti- Programmed cell death protein1 (PD-1) antibody significantly reduced cardiac function in C57BL/6J mice, and this pathologic effect was aggravated by anti-PD-1 (anti-PD-1 + radiation). To examine the cellular mechanism that causes the detrimental effect of anti-PD-1 upon cardiac function after radiation, AC16 human cardiomyocytes were used to study cardiac apoptosis and cardiac autophagy. Radiation-induced cardiomyocyte apoptosis was significantly promoted by anti-PD-1 treatment, while anti-PD-1 combined radiation administration blocked the cardiac autophagic flux. Adenosine 5'-triphosphate (ATP) (a molecule that promotes lysosomal acidification) not only improved autophagic flux in AC16 human cardiomyocytes, but also attenuated apoptosis induced by radiation and anti-PD-1 treatment. Finally, ATP administration in vivo significantly reduced radiation-induced and anti-PD-1-exacerbated cardiac dysfunction. We demonstrated for the first time that anti-PD-1 can aggravate radiation-induced cardiac dysfunction via promoting cardiomyocyte apoptosis without affecting radiation-arrested autophagic flux. ATP enhanced cardiomyocyte autophagic flux and inhibited apoptosis, improving cardiac function in anti-PD-1/radiation combination-treated animals.

Dysfunctional APPL1-Mediated Epigenetic Regulation in Diabetic Vascular Injury.

BACKGROUND: APN (adiponectin) and APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) are potent vasculoprotective molecules, and their deficiency (eg, hypoadiponectinemia) contributes to diabetic vascular complications. However, the molecular mechanisms that govern their vasculoprotective genes as well as their alteration by diabetes remain unknown. METHODS: Diabetic medium-cultured rat aortic endothelial cells, mouse aortic endothelial cells from high-fat-diet animals, and diabetic human aortic endothelial cells were used for molecular/cellular investigations. The in vivo concept-prove demonstration was conducted using diabetic vascular injury and diabetic hindlimb ischemia models. RESULTS: In vivo animal experiments showed that APN replenishment caused APPL1 nuclear translocation, resulting in an interaction with HDAC (histone deacetylase) 2, which inhibited HDAC2 activity and increased H3Kac27 levels. Based on transcriptionome pathway-specific real-time polymerase chain reaction profiling and bioinformatics analysis, Angpt1 (angiopoietin 1), Ocln (occludin), and Cav1 (caveolin 1) were found to be the top 3 vasculoprotective genes suppressed by diabetes and rescued by APN in an APPL1-dependent manner. APN reverses diabetes-induced inhibition of Cav1 interaction with APPL1. APN-induced Cav1 expression was not affected by Angpt1 or Ocln deficiency, whereas APN-induced APPL1 nuclear translocation or upregulation of Angpt1/Ocln expression was abolished in the absence of Cav1 both in vivo and in vitro, suggesting Cav1 is upstream molecule of Angpt1/Ocln in response to APN administration. Chromatin immunoprecipitation-qPCR (quantitative polymerase chain reaction) demonstrated that APN caused significant enrichment of H3K27ac in Angpt1 and Ocln promoter region, an effect blocked by APPL1/Cav1 knockdown or HDAC2 overexpression. The protective effects of APN on the vascular system were attenuated by overexpression of HDAC2 and abolished by knocking out APPL1 or Cav1. The double knockdown of ANGPT1/OCLN blunted APN vascular protection both in vitro and in vivo. Furthermore, in diabetic human endothelial cells, HDAC2 activity is increased, H3 acetylation is decreased, and ANGPT1/OCLN expression is reduced, suggesting that the findings have important translational implications. CONCLUSIONS: Hypoadiponectinemia and dysregulation of APPL1-mediated epigenetic regulation are novel mechanisms leading to diabetes-induced suppression of vasculoprotective gene expression. Diabetes-induced pathological vascular remodeling may be prevented by interventions promoting APPL1 nuclear translocation and inhibiting HDAC2.

Enhanced biological wastewater treatment supplemented with anaerobic fermentation liquid of primary sludge.

The wastewater treatment performance in an inverted A2/O reactor supplemented with fermentation liquid of primary sludge was explored comparing to commercial carbon sources sodium acetate and glucose. Similar COD removal rate was observed with the effluent COD stably reaching the discharge standard for those 3 carbon sources. However, the fermentation liquid distributed more carbon source in the anaerobic zone. Fermentation liquid and sodium acetate tests achieved better nitrogen removal rate than glucose test. The fermentation liquid test showed the best biological phosphorus removal performance with the effluent phosphorus barely reaching the discharge standard. The microbial community characterization revealed that the fermentation liquid test was dominated by phylum Proteobacter in all the anoxic, anaerobic and aerobic zones. Denitrifying phosphorus accumulating organisms (PAOs) (i.e., genera Dechloromonas and unclassified_f__Rhodocyclaceae) were selectively enriched with high abundances (over 20%), which resulted in improved phosphorus removal efficiency. Moreover, the predicted abundances of enzymes involved in nitrogen and phosphorus removal were also enhanced by the fermentation liquid.

Single-cell communication patterns and their intracellular information flow in synovial fibroblastic osteoarthritis and rheumatoid arthritis.

BACKGROUND: Synovial fibroblasts are critical for maintaining homeostasis in major autoimmune diseases involving joint inflammation, including osteoarthritis and rheumatoid arthritis. However, little is known about the interactions among different cell subtypes and the specific sets of signaling pathways and activities that they trigger. METHODS: Using social network analysis, pattern recognition, and manifold learning approaches, we identified patterns of single-cell communication in OA (osteoarthritis) and RA (rheumatoid arthritis). RESULTS: Our results suggest that OA and RA have distinct cellular communication patterns and signaling pathways. The LAMININ (Laminin) and COLLAGEN (Collagen) pathways predominate in osteoarthritis, while the EGF (Epidermal growth factor), NT (Neurotrophin) and CDH5 (Cadherin 5) pathways predominate in rheumatoid arthritis, with a central role for THY1 (Thy-1 cell surface antigen) +CDH11 (Cadherin 11) + cells. The OA opens the PDGF (Platelet-derived growth factors) pathway (driver of bone angiogenesis), the RA opens the EGF pathway (bone formation) and the SEMA3 (Semaphorin 3A) pathway (involved in immune regulation). Interestingly, we found that OA no longer has cell types involved in the MHC complex (Major histocompatibility complex) and their activity, whereas the MHC complex functions primarily in RA in the presentation of inflammatory antigens, and that the complement system in OA has the potential to displace the function of the MHC complex. The specific signaling patterns of THY1+CDH11+ cells and their secreted ligand receptors are more conducive to cell migration and lay the foundation for promoting osteoclastogenesis. This subpopulation may also be involved in the accumulation of lymphocytes, affecting the recruitment of immune cells. Members of the collagen family (COL1A1 (Collagen Type I Alpha 1 Chain), COL6A2 (Collagen Type VI Alpha 2 Chain) and COL6A1 (Collagen Type VI Alpha 1 Chain)) and transforming growth factor (TGFB3) maintain the extracellular matrix in osteoarthritis and mediate cell migration and adhesion in rheumatoid arthritis, including the PTN (Pleiotrophin) / THBS1 (Thrombospondin 1) interaction. CONCLUSION: Increased understanding of the interaction networks between synovial fibroblast subtypes, particularly the shared and unique cellular communication features between osteoarthritis and rheumatoid arthritis and their hub cells, should help inform the design of therapeutic agents for inflammatory joint disease.

Probing the communication patterns of different chondrocyte subtypes in osteoarthritis at the single cell level using pattern recognition and manifold learning.

The patterns of communication among different chondrocyte subtypes in human cartilage degeneration and regeneration help us understand the microenvironment of osteoarthritis and optimize cell-targeted therapies. Here, a single-cell transcriptome dataset of chondrocytes is used to explore the synergistic and communicative patterns of different chondrocyte subtypes. We collected 1600 chondrocytes from 10 patients with osteoarthritis and analyzed the active communication patterns for the first time based on network analysis and pattern recognition at the single-cell level. Manifold learning and quantitative contrasts were performed to analyze conserved and specific communication pathways. We found that ProCs (Proliferative chondrocytes), ECs (Effector chondrocytes), preHTCs (Prehypertrophic chondrocytes), HTCs (Hypertrophic chondrocytes), and FCs (Fibrocartilage chondrocytes) are more active in incoming and outgoing signaling patterns, which is consistent with studies on their close functional cooperation. Among them, preHTCs play multiple roles in chondrocyte communication, and ProCs and preHTCs have many overlapping pathways. These two subtypes are the most active among all chondrocyte subtypes. Interestingly, ECs and FCs are a pair of "mutually exclusive" subtypes, of which ECs are predominant in incoming patterns and FCs in outgoing patterns. The active signaling pathways of ECs and FCs largely do not overlap. COLLAGEN and LAMININ are the main pivotal pathways, which means they are very important in the repair and expansion of joint homeostasis. Notably, only preHTCs assume multiple roles (including sender, receiver, mediator, and influencer) and are involved in multiple communication pathways. We have examined their communication patterns from the perspective of cellular interactions, revealed the relationships among different chondrocyte subtypes, and, in particular, identified a number of active subtypes and pathways that are important for targeted therapy in the osteoarthritic microenvironment. Our findings provide a new research paradigm and new insights into understanding chondrocyte activity patterns in the osteoarthritic microenvironment.

RNA-Sequencing and Bioinformatics Analysis of Exosomal Long Noncoding RNAs Revealed a Novel ceRNA Network in Stable COPD.

Purpose: Exosomes are able to exchange their bioactive RNA cargo to recipient cells. In COPD, exosomes can be controlled and engineered for its use as targeted diagnostic and therapeutic tool. Our study explored novel lncRNAs and mRNAs in plasma exosomes that could be involved in the pathogenesis of COPD. Methods: High-throughput sequencing was conducted to detect the alterations in the expression of exosomal lncRNAs and mRNAs. Gene ontology (GO) functional analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to determine the significant functions and pathways associated with differentially expressed (DE) lncRNAs. The mRNA expression profile dataset, GSE76925, and microRNA expression profile dataset, GSE70080, were obtained from the GEO database. Venn diagrams were used to find common DE mRNAs between my mRNAs dataset and GSE76925. These common DEGs were subjected to PPI analyses to identify Hub genes. Subsequently, Venn diagrams were used to identify common genes between the target genes of DE-miRNAs and Hub genes as well as DE-miRNAs and my lncRNAs dataset. Finally, a lncRNA-miRNA-mRNA co-expression network was constructed by prediction using proprietary software. The lncRNA and mRNA expressions were then validated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Results: We identified 1578 differentially regulated lncRNAs and 3071 differentially regulated mRNAs. GO and KEGG pathway analyses suggested that the DE lncRNAs are involved in the pathogenesis of COPD. A lncRNA-miRNA-mRNA meshwork was established to predict the potential interactions among these RNAs. RP3-329A5.8 and MRPS11 expression was then subjected to qRT-PCR for validation. Correlations between MRPS11 and clinic-pathological features were explored. Conclusion: Our study provided a set of lncRNAs and mRNAs that may be involved in the pathogenesis of COPD, thereby highlighting the need for further research on both diagnostic biomarkers and molecular mechanisms.

Hypoadiponectinemia-induced upregulation of microRNA449b downregulating Nrf-1 aggravates cardiac ischemia-reperfusion injury in diabetic mice.

Diabetes enhances myocardial ischemic/reperfusion (MI/R) injury via an incompletely understood mechanism. Adiponectin (APN) is a cardioprotective adipokine suppressed by diabetes. However, how hypoadiponectinemia exacerbates cardiac injury remains incompletely understood. Dysregulation of miRNAs plays a significant role in disease development. However, whether hypoadiponectinemia alters cardiac miRNA profile, contributing to diabetic heart injury, remains unclear. Methods and Results: Wild-type (WT) and APN knockout (APN-KO) mice were subjected to MI/R. A cardiac microRNA profile was determined. Among 23 miRNAs increased in APN-KO mice following MI/R, miR-449b was most significantly upregulated (3.98-fold over WT mice). Administrating miR-449b mimic increased apoptosis, enlarged infarct size, and impaired cardiac function in WT mice. In contrast, anti-miR-449b decreased apoptosis, reduced infarct size, and improved cardiac function in APN-KO mice. Bioinformatic analysis predicted 73 miR-449b targeting genes, and GO analysis revealed oxidative stress as the top pathway regulated by these genes. Venn analysis followed by luciferase assay identified Nrf-1 and Ucp3 as the two most important miR-449b targets. In vivo administration of anti-miR-449b in APN-KO mice attenuated MI/R-stimulated superoxide overproduction. In vitro experiments demonstrated that high glucose/high lipid and simulated ischemia/reperfusion upregulated miR-449b and inhibited Nrf-1 and Ucp3 expression. These pathological effects were attenuated by anti-miR-449b or Nrf-1 overexpression. In a final attempt to validate our finding in a clinically relevant model, high-fat diet (HFD)-induced diabetic mice were subjected to MI/R and treated with anti-miR-449b or APN. Diabetes significantly increased miR-449b expression and downregulated Nrf-1 and Ucp3 expression. Administration of anti-miR-449b or APN preserved cardiac Nrf-1 expression, reduced cardiac oxidative stress, decreased apoptosis and infarct size, and improved cardiac function. Conclusion: We demonstrated for the first time that hypoadiponectinemia upregulates miR-449b and suppresses Nrf-1/Ucp3 expression, promoting oxidative stress and exacerbating MI/R injury in this population. Dysregulated APN/miR-449b/oxidative stress pathway is a potential therapeutic target against diabetic MI/R injury.

Incidence and risk factors of acute kidney injury in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: The incidence and risk factors of acute kidney injury (AKI) in patients with malignancies receiving immune checkpoint inhibitors (ICIs) are being extensively reported with their widespread application. Objective: This study aimed to quantify the incidence and identify risk factors of AKI in cancer patients treated with ICIs. Methods: We searched the electronic databases of PubMed/Medline, Web of Science, Cochrane and Embase before 1 February 2023 on the incidence and risk factors of AKI in patients receiving ICIs and registered the protocol in PROSPERO (CRD42023391939). A random-effect meta-analysis was performed to quantify the pooled incidence estimate of AKI, identify risk factors with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) and investigate the median latency period of ICI-AKI in patients treated with ICIs. Assessment of study quality, meta-regression, and sensitivity and publication bias analyses were conducted. Results: In total, 27 studies consisting of 24048 participants were included in this systematic review and meta-analysis. The overall pooled incidence of AKI secondary to ICIs was 5.7% (95% CI: 3.7%-8.2%). Significant risk factors were older age (OR: 1.01, 95% CI: 1.00-1.03), preexisting chronic kidney disease (CKD) (OR: 2.90, 95% CI: 1.65-5.11), ipilimumab (OR: 2.66, 95% CI: 1.42-4.98), combination of ICIs (OR: 2.45, 95% CI: 1.40-4.31), extrarenal immune-related adverse events (irAEs) (OR: 2.34, 95% CI: 1.53-3.59), and proton pump inhibitor (PPI) (OR: 2.23, 95% CI: 1.88-2.64), nonsteroidal anti-inflammatory drug (NSAID) (OR: 2.61, 95% CI: 1.90-3.57), fluindione (OR: 6.48, 95% CI: 2.72-15.46), diuretic (OR: 1.78, 95% CI: 1.32-2.40) and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) (pooled OR: 1.76, 95% CI: 1.15-2.68) use. Median time from ICIs initiation to AKI was 108.07 days. Sensitivity and publication bias analyses indicated robust results for this study. Conclusion: The occurrence of AKI following ICIs was not uncommon, with an incidence of 5.7% and a median time interval of 108.07 days after ICIs initiation. Older age, preexisting chronic kidney disease (CKD), ipilimumab, combined use of ICIs, extrarenal irAEs, and PPI, NSAID, fluindione, diuretics and ACEI/ARB use are risk factors for AKI in patients receiving ICIs. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023391939.

Reduction of Membrane Lipid Metabolism in Postharvest Hami Melon Fruits by n-Butanol to Mitigate Chilling Injury and the Cloning of Phospholipase D-ß Gene.

To investigate the effect of n-butanol on postharvest membrane lipid metabolism of Hami melon (Cucumis melo 'Hami'), the fruits were soaked in a 1.0% solution of n-butanol for 30 min with water as the control. Symptoms of chilling injury were observed regularly, and the indices related to permeability and membrane lipid metabolism of pericarp cells were measured. The results showed that treatment with n-butanol inhibited the increase in chilling injury index, membrane permeability, and malondialdehyde content of Hami melon fruits, promoted an increase in the contents of phosphatidyl alcohol and unsaturated fatty acids, such as linoleic acid, linolenic acid, oleic acid (except 14 d), and erucic acid (28-42 d), and decreased the content of saturated fatty acids, stearic acid (0-28 d), phosphatidic acid (except for 21 d), and the key enzymes of membrane lipid metabolism compared with the control. The activities of phospholipase D (PLD) and lipoxygenase (LOX) and the downregulation of the levels of expression CmPLD-ß and CmLOX (42 d only) genes reduced the chilling injury index of Hami melon and alleviated the further expansion of chilling injury symptoms in the fruits. We also cloned the key gene of membrane lipid metabolism CmPLD-ß, which was obtained by pre-transcriptome screening of the pericarp. We found that CmPLD-ß of Hami melon had the closest affinity with cucumber (CsXP5), indicating that the CmPLD-ß gene of Hami melon was functionally similar to that of cucumber. In addition, a two-fold alignment analysis of CmPLD-ß and CmXP5 base sequences indicated that the base sequences of the two promoter regions differed from each other.

EPC-exosomal miR-26a-5p improves airway remodeling in COPD by inhibiting ferroptosis of bronchial epithelial cells via PTGS2/PGE2 signaling pathway.

We aimed to investigate whether exosomes (Exo) affected chronic obstructive pulmonary disease (COPD) by influencing ferroptosis of bronchial epithelial cells (BECs) and the mechanisms involved. Here we took the peripheral blood samples of normal subjects and COPD patients, extracted and identified endothelial progenitor cells (EPCs) and EPC-Exo. An animal model of COPD was established. Then human BECs were taken and treated with cigarette smoke extract (CSE) for 24 h to construct a COPD cell model. Next, we screened differentially expressed ferroptosis-related genes in COPD patients by bioinformatics. Bioinformatics predicted the miRNA targeting PTGS2. Then, the mechanism of action of miR-26a-5p and Exo-miR-26a-5p was investigated in vitro. We successfully isolated and identified EPC and Exo. In vitro, EPC alleviated CSE-induced ferroptosis in BECs by transporting Exo. In vivo, Exo alleviated cigarette smoke-induced ferroptosis and airway remodeling in mice. Through further validation, we found that CSE-induced ferroptosis promoted the epithelial-mesenchymal transition (EMT) of BECs. Bioinformatics analysis and validation showed that PTGS2/PGE2 pathway affected CSE-induced ferroptosis in BECs. Meanwhile, miR-26a-5p targeting PTGS2 affected CSE-induced ferroptosis in BECs. Additionally, we found that miR-26a-5p affected CSE-induced BECs EMT. Exo-miR-26a-5p alleviated CSE-induced ferroptosis and EMT. In conclusion, EPC-exosomal miR-26a-5p improved airway remodeling in COPD by inhibiting ferroptosis of BECs via the PTGS2/PGE2 pathway.

Phytoextraction of per- and polyfluoroalkyl substances (PFAS) by weeds: Effect of PFAS physicochemical properties and plant physiological traits.

Phytoextraction is a promising technology that uses plants to remediate contaminated soil. However, its feasibility for per- and polyfluoroalkyl substances (PFAS) and the impact of PFAS properties and plant traits on phytoextraction efficacy remains unknown. In this study, we conducted greenhouse experiment and evaluated the potential of weeds for phytoextraction of PFAS from soil and assessed the effects of PFAS properties and plant traits on PFAS uptake via systematic correlation analyses and electron probe microanalyzer with energy dispersive spectroscopy (FE-EPMA-EDS) imaging. The results showed that 1) phytoextraction can remove 0.04%- 41.4%wt of PFAS from soil, with extracted PFAS primarily stored in plant shoots; 2) Weeds preferentially extracted short-chain PFAS over long-chain homologues from soil. 3) PFAS molecular size and hydrophilicity determined plant uptake behavior, while plant morphological traits, particularly root protein and lipid content, influenced PFAS accumulation and translocation. Although plants with thin roots and small leaf areas exhibited greater PFAS uptake and storage ability, the impact of PFAS physicochemical properties was more significant. 4) Finally, short-chain PFAS were transported quickly upwards in the plant, while uptake of long-chain PFOS was restricted.

Removal of per- and polyfluoroalkyl substances by nanofiltration: Effect of molecular structure and coexisting natural organic matter.

This study investigates the removal efficiency of anionic, cationic, and zwitterionic per- and polyfluoroalkyl substances (PFAS) by nanofiltration (NF) in the presence of three representative natural organic matter (NOM) types: bovine serum albumin (BSA), humic acid (HA), and sodium alginate (SA). In particular, effects of PFAS molecular structure and coexisting NOM on the transmission and adsorption efficiency of PFAS during NF treatment were analyzed. The results indicate that NOM types dominate membrane fouling behavior despite the coexistence of PFAS. SA exhibits the most significant fouling propensity, resulting in maximum water flux decline. NF effectively removed both ether and precursor PFAS. The effects of the three typical NOM on the membrane-passing behavior of PFAS were consistent for all PFAS investigated. Generally, PFAS transmission decreased in the order of SA-fouled > pristine > HA-fouled > BSA-fouled, indicating that the presence of HA and BSA enhanced PFAS removal while SA declined. Furthermore, reduced PFAS transmission was observed with increased perfluorocarbon chain length or molecular weight (MW), regardless of the presence or type of the NOM. The impacts of NOM on PFAS filtration diminished when the PFAS van der Waals radius was > 4.0 Å, MW > 500 Da, polarization > 20 Å, or LogKow > 3. These findings suggest that both steric repulsion and hydrophobic interactions, especially the former, play important roles in PFAS rejection by NF. This study provides insights into the specific applicability and performance of membrane-based processes for eliminating PFAS during drinking and wastewater treatments, and highlighting the importance of coexisting NOM.