Effect of music on hemodynamic fluctuations in women during induction of general anesthesia: A prospective randomized controlled multicenter trial.

BACKGROUND: The authors aim to investigate the effect of music on hemodynamic fluctuations during induction of general anesthesia and reducing preoperative anxiety for women who underwent elective non-cardiac surgery. METHODS: It is a multicenter, double-blind, randomized, parallel-group clinical trial. Patients were randomized 1:1 to either a Music Intervention group (MI) or a Control group (Control). The MI participants listened to their preferred music for more than 30 minutes in the waiting area. The State-Trait Anxiety Inventory (STAI) was used to measure anxiety levels in the groups, and hemodynamic parameters (Heart Rate [HR], Mean Arterial Pressure [MAP]) were continuously recorded before induction (T0), at loss of consciousness (T1), immediately before intubation (T2), and after intubation (T3). Intubation-related adverse events were also recorded. The primary outcome was the incidence of MAP changes more than 20 % above baseline during T0-T2. RESULTS: A total of 164 patients were included in the final analyses. The incidence of MAP instability during T0-T2 was lower in the MI, and the 95 % Confidence Interval for the rate difference demonstrated the superiority of MI. HR instability was less frequent in MI participants both in T0-T2 and T2-T3. The overall incidence of preoperative anxiety was 53.7 % (88/164). After the music intervention, the mean score of STAI was significantly lower in the MI than in the Control, with a between-group difference of 8.01. CONCLUSIONS: Preoperative music intervention effectively prevented hemodynamic instability during anesthesia induction and significantly reduced preoperative anxiety in women undergoing elective non-cardiac surgery.

Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.

Perioperative NETosis and Cancer Progression: Current Evidence and Future Perspectives.

PURPOSE OF REVIEW: The process of neutrophil extracellular traps (NETs) formation, called NETosis, is a peculiar death modality of neutrophils, which was first observed as an immune response against bacterial infection. However, an ongoing and exaggerated NETs formation may have adverse clinical consequences and even promote cancer progression. This review will discuss the complex relationship between NETosis and cancer progression. RECENT FINDINGS: NETs exhibits cancer-promoting effects by causing cancer metastaisis and tumor-associated thrombosis. Many studies have found that many mechanisms are involved in the process, and the corresponding targets could be applied for cancer therapy. Although NETs may have anti-bacteria effects, it is necessary to inhibit an excessive NETs formation, mostly showing cancer-promoting effects. The contribution of NETs to cancer progression has gained a growing appreciation and the approaches to targeting NETs deposition exhibited beneficial effects both in primary and metastatic tumors, which, however, has been challenged by a recent finding demonstrating an opposite effect of NETs to suppress tumor growth via the activation of immune response against tumor. This seeming discrepancy reflects we are in the early stage of NETs study facing fundamental questions and a better understanding of the underlying mechanism is urgently needed.

ZIPK collaborates with STAT5A in p53-mediated ROS accumulation in hyperglycemia-induced vascular injury.

In this study we investigate the role of Zipper-interacting protein kinase (ZIPK) in high glucose-induced vascular injury, focusing on its interaction with STAT5A and its effects on p53 and inducible nitric oxide synthase (NOS2) expression. Human umbilical vein endothelial cells (HUVECs) are cultured under normal (5 mM) and high (25 mM) glucose conditions. Protein and gene expression levels are assessed by western blot analysis and qPCR respectively, while ROS levels are measured via flow cytometry. ZIPK expression is manipulated using overexpression plasmids, siRNAs, and shRNAs. The effects of the ZIPK inhibitor TC-DAPK6 are evaluated in a diabetic rat model. Our results show that high glucose significantly upregulates ZIPK, STAT5A, p53, and NOS2 expressions in HUVECs, thus increasing oxidative stress. Silencing of STAT5A reduces p53 and NOS2 expressions and reactive oxygen species (ROS) accumulation. ZIPK is essential for high glucose-induced p53 expression and ROS accumulation, while silencing of ZIPK reverses these effects. Overexpression of ZIPK combined with STAT5A silencing attenuates glucose-induced alterations in p53 and NOS2 expression, thereby preventing cell damage. Coimmunoprecipitation reveals a direct interaction between ZIPK and STAT5A in the nucleus under high-glucose condition. In diabetic rats, TC-DAPK6 treatment significantly decreases ZIPK, p53, and NOS2 expressions. Our findings suggest that ZIPK plays a critical role in high glucose-induced vascular injury via STAT5A-mediated pathways, proposing that ZIPK is a potential therapeutic target for diabetic vascular complications.

Exploring biomarkers for diagnosing and predicting organ dysfunction in patients with perioperative sepsis: a preliminary investigation.

OBJECTIVE: Early diagnosis and prediction of organ dysfunction are critical for intervening and improving the outcomes of septic patients. The study aimed to find novel diagnostic and predictive biomarkers of organ dysfunction for perioperative septic patients. METHOD: This is a prospective, controlled, preliminary, and single-center study of emergency surgery patients. Mass spectrometry, Gene Ontology (GO) functional analysis, and the protein-protein interaction (PPI) network were performed to identify the differentially expressed proteins (DEPs) from sepsis patients, which were selected for further verification via enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to estimate the relative correlation of selected serum protein levels and clinical outcomes of septic patients. Calibration curves were plotted to assess the calibration of the models. RESULTS: Five randomized serum samples per group were analyzed via mass spectrometry, and 146 DEPs were identified. GO functional analysis and the PPI network were performed to evaluate the molecular mechanisms of the DEPs. Six DEPs were selected for further verification via ELISA. Cathepsin B (CatB), vascular cell adhesion protein 1 (VCAM-1), neutrophil gelatinase-associated lipocalin (NGAL), protein S100-A9, prosaposin, and thrombospondin-1 levels were significantly increased in the patients with sepsis compared with those of the controls (p < 0.001). Logistic regression analysis showed that CatB, S100-A9, VCAM-1, prosaposin, and NGAL could be used for preoperative diagnosis and postoperative prediction of organ dysfunction. CatB and S100-A9 were possible predictive factors for preoperative diagnosis of renal failure in septic patients. Internal validation was assessed using the bootstrapping validation. The preoperative diagnosis of renal failure model displayed good discrimination with a C-index of 0.898 (95% confidence interval 0.843-0.954) and good calibration. CONCLUSION: Serum CatB, S100-A9, VCAM-1, prosaposin, and NGAL may be novel markers for preoperative diagnosis and postoperative prediction of organ dysfunction. Specifically, S100-A9 and CatB were indicators of preoperative renal dysfunction in septic patients. Combining these two biomarkers may improve the accuracy of predicting preoperative septic renal dysfunction. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trials Registry (ChiCTR2200060418) on June 1, 2022.

Structural basis of antagonist selectivity in endothelin receptors.

Endothelins and their receptors, ETA and ETB, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ETA antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ETA in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ETA antagonist, respectively. Notably, a specialized anti-ETA antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ETA and ETB, and the agonist BQ3020-bound ETB, in complex with Gq, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ETA. Furthermore, our results suggest that ECL2 in ETA can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors.

Regulatory T-cell and neutrophil extracellular traps interaction contributes to the development of immunosuppression in sepsis.

The excessive formation and release of neutrophil extracellular traps (NETs) in sepsis may represent a substantial mechanism contributing to multi-organ damage, which is associated with a poorer prognosis. However, the precise role of NETs in mediating the transition from innate immunity to adaptive immunity during the progression of inflammation and sepsis remains incompletely elucidated. In this study, we provide evidence that, despite a reduction in the number of CD4+ T-cells in the late stage of sepsis, there is a notable upregulation in the proportion of regulatory T-cells (Tregs). Mechanistically, we have identified that NETs can induce metabolic reprogramming of naïve CD4+ T-cells through the Akt-mTOR-SREBP2 pathway, resulting in enhanced cholesterol metabolism, thereby promoting their conversion into Tregs and augmenting their functional capacity. Collectively, our findings highlight the potential therapeutic strategy of targeting intracellular cholesterol normalization for the management of immunosuppressed patients with sepsis.

S100A8/A9hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis.

S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory diseases. Although S100a8/a9 has been reported to trigger endothelial cell apoptosis, the mechanisms of S100a8/a9-induced endothelial dysfunction during sepsis require in-depth research. We demonstrate that high expression levels of S100a8/a9 suppress Ndufa3 expression in mitochondrial complex I via downregulation of Nrf1 expression. Mitochondrial complex I deficiency contributes to NAD+-dependent Sirt1 suppression, which induces mitochondrial disorders, including excessive fission and blocked mitophagy, and mtDNA released from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis in endothelial cells. Moreover, based on comprehensive scRNA-seq and bulk RNA-seq analyses, S100A8/A9hi neutrophils are closely associated with the circulating endothelial cell count (a useful marker of endothelial damage), and S100A8 is an independent risk factor for poor prognosis in sepsis patients.

Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury.

Elevated lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is a leading cause of poor prognosis in clinical patients. However, the underlying mechanisms of lactate's involvement in sepsis-associated ALI remain unclear. In this study, we demonstrate that lactate regulates N6-methyladenosine (m6A) modification levels by facilitating p300-mediated H3K18la binding to the METTL3 promoter site. The METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Furthermore, short-term lactate stimulation upregulates ACSL4, which promotes mitochondria-associated ferroptosis. Inhibition of METTL3 through knockdown or targeted inhibition effectively suppresses septic hyper-lactate-induced ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. Our findings suggest that lactate induces ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI. These results reveal a histone lactylation-driven mechanism inducing ferroptosis through METTL3-mediated m6A modification. Targeting METTL3 represents a promising therapeutic strategy for patients with sepsis-associated ALI.

Predicting Chronic Pain and Treatment Outcomes Using Machine Learning Models Based on High-dimensional Clinical Data From a Large Retrospective Cohort.

PURPOSE: To identify factors and indicators that affect chronic pain and pain relief, and to develop predictive models using machine learning. METHODS: We analyzed the data of 67,028 outpatient cases and 11,310 valid samples with pain from a large retrospective cohort. We used decision tree, random forest, AdaBoost, neural network, and logistic regression to discover significant indicators and to predict pain and treatment relief. FINDINGS: The random forest model had the highest accuracy, F1 value, precision, and recall rates for predicting pain relief. The main factors affecting pain and treatment relief included body mass index, blood pressure, age, body temperature, heart rate, pulse, and neutrophil/lymphocyte × platelet ratio. The logistic regression model had high sensitivity and specificity for predicting pain occurrence. IMPLICATIONS: Machine learning models can be used to analyze the risk factors and predictors of chronic pain and pain relief, and to provide personalized and evidence-based pain management.

Deficiency of UCHL1 results in insufficient decidualization accompanied by impaired dNK modulation and eventually miscarriage.

BACKGROUND: Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown. METHODS: With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7-10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome. RESULTS: The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-ß which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome. CONCLUSIONS: UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage.

Sirt7/HIC1 complex participates in hyperglycaemia-mediated EndMT via modulation of SDC1 expression in diabetic kidney disease and metabolic memory.

Diabetic kidney disease (DKD), a primary microvascular complication arising from diabetes, may result in end-stage renal disease. Epigenetic regulation of endothelial mesenchymal transition (EndMT) has been recently reported to exert function in metabolic memory and DKD. Here, we investigated the mechanism which Sirt7 modulated EndMT in human glomerular endothelial cells (HGECs) in the occurrence of metabolic memory in DKD. Lower levels of SDC1 and Sirt7 were noted in the glomeruli of both DKD patients and diabetes-induced renal injury rats, as well as in human glomerular endothelial cells (HGECs) with high blood sugar. Endothelial-to-mesenchymal transition (EndMT) was sustained despite the normalization of glycaemic control. We also found that Sirt7 overexpression associated with glucose normalization promoted the SDC1 expression and reversed EndMT in HGECs. Furthermore, the sh-Sirt7-mediated EndMT could be reversed by SDC1 overexpression. The ChIP assay revealed enrichment of Sirt7 and H3K18ac in the SDC1 promoter region. Furthermore, hypermethylated in cancer 1 (HIC1) was found to be associated with Sirt7. Overexpression of HIC1 with normoglycaemia reversed high glucose-mediated EndMT in HGECs. The knockdown of HIC1-mediated EndMT was reversed by SDC1 upregulation. In addition, the enrichment of HIC1 and Sirt7 was observed in the same promoter region of SDC1. The overexpressed Sirt7 reversed EndMT and improved renal function in insulin-treated diabetic models. This study demonstrated that the hyperglycaemia-mediated interaction between Sirt7 and HIC1 exerts a role in the metabolic memory in DKD by inactivating SDC1 transcription and mediating EndMT despite glucose normalization in HGECs.

Low Pneumoperitoneum Pressure Reduces Gas Embolism During Laparoscopic Liver Resection: A Randomized Controlled Trial.

OBJECTIVE: To compare the effect of low and standard pneumoperitoneal pressure (PP) on the occurrence of gas embolism during laparoscopic liver resection (LLR). BACKGROUND: LLR has an increased risk of gas embolism. Although animal studies have shown that low PP reduces the occurrence of gas embolism, clinical evidence is lacking. METHODS: This parallel, dual-arm, double-blind, randomized controlled trial included 141 patients undergoing elective LLR. Patients were randomized into standard ("S," 15 mm Hg; n = 70) or low ("L," 10 mm Hg; n = 71) PP groups. Severe gas embolism (≥ grade 3, based on the Schmandra microbubble method) was detected using transesophageal echocardiography and recorded as the primary outcome. Intraoperative vital signs and postoperative recovery profiles were also evaluated. RESULTS: Fewer severe gas embolism cases (n = 29, 40.8% vs n = 47, 67.1%, P = 0.003), fewer abrupt decreases in end-tidal carbon dioxide partial pressure, shorter severe gas embolism duration, less peripheral oxygen saturation reduction, and fewer increases in heart rate and lactate during gas embolization episodes was found in group L than in group S. Moreover, a higher arterial partial pressure of oxygen and peripheral oxygen saturation were observed, and fewer fluids and vasoactive drugs were administered in group L than in group S. In both groups, the distensibility index of the inferior vena cava negatively correlated with central venous pressure throughout LLR, and a comparable quality of recovery was observed. CONCLUSIONS: Low PP reduced the incidence and duration of severe gas embolism and achieved steadier hemodynamics and vital signs during LLR. Therefore, a low PP strategy can be considered a valuable choice for the future LLR.

Prospects of molecular hydrogen in cancer prevention and treatment.

Gas signaling molecules, including carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), have been shown to have cancer therapeutic potential, pointing to a new direction for cancer treatment. In recent years, a series of studies have confirmed that hydrogen (H2), a weakly reductive gas, also has therapeutic effects on various cancers and can mitigate oxidative stress caused by radiation and chemotherapy, reducing tissue damage and immunosuppression to improve prognosis. Meanwhile, H2 also has immunomodulatory effects, inhibiting T cell exhaustion and enhancing T cell anti-tumor function. It is worth noting that human intestinal flora can produce large amounts of H2 daily, which becomes a natural barrier to maintaining the body's resistance to diseases such as tumors. Although the potential anti-tumor mechanisms of H2 are still to be investigated, previous studies have shown that H2 can selectively scavenge highly toxic reactive oxygen species (ROS) and inhibit various ROS-dependent signaling pathways in cancer cells, thus inhibiting cancer cell proliferation and metastasis. The ROS scavenging ability of H2 may also be the underlying mechanism of its immunomodulatory function. In this paper, we review the significance of H2 produced by intestinal flora on the immune homeostasis of the body, the role of H2 in cancer therapy and the underlying mechanisms, and the specific application of H2 to provide new ideas for the comprehensive treatment of cancer patients.

Association between triglyceride-glucose index and acute kidney injury in patients with acute myocardial infarction based on medical information mart for intensive care database: A cross-sectional study.

Background: The relationship between triglyceride glucose (TyG) index and the incidence of acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) is unclear. This study aims to explore the relationship between the two. Methods: Participants were enrolled from Medical Information Mart for Intensive Care IV (MIMICIV) and grouping of subjects based on the quartile interval of the TyG index. With the presence of AKI as the main outcome, a logistic regression model was constructed. The correlation of the TyG index with the results obtained was examined by using a restricted cubic spline (RCS) model.

HSK3486 Inhibits Colorectal Cancer Growth by Promoting Oxidative Stress and ATPase Inhibitory Factor 1 Activation.

BACKGROUND: HSK3486 (ciprofol), a new candidate drug similar to propofol, exerts sedative and hypnotic effects through gamma-aminobutyric acid type A receptors; however, its potential role in colorectal cancer is currently unknown. AIMS: This study aimed to evaluate the effects of HSK3486 on colorectal cancer cell proliferation. METHODS: Imaging was performed to detect reactive oxygen species and mitochondrial membrane potential. Western blotting was used to determine the expression of target signals. The HSK3486 molecular mechanism was investigated through ATPase inhibitory factor 1 knockdown and xenograft model experiments to assess mitochondrial function in colorectal cancer cells. RESULTS: Cell Counting Kit-8 and Annexin V/propidium iodide double staining assays showed that HSK3486 inhibited colorectal cancer cell proliferation in a concentration-dependent manner. In addition, HSK3486 treatment increased the expression of B-cell lymphoma-2-associated X, cleaved caspase 3, and cleaved poly (ADP-ribose) polymerase, whereas myeloid cell leukemia-1 and B-cell lymphoma 2 expression decreased. HSK3486 promoted mitochondrial dysfunction by inducing ATPase inhibitor factor 1 expression. Furthermore, HSK3486 promoted oxidative stress, as shown by the increase in reactive oxygen species and lactate dehydrogenase levels, along with a decrease in mitochondrial membrane potential and ATP levels. ATPase inhibitor factor 1 small interfering RNA pretreatment dramatically increased the mitochondrial membrane potential and tumor size in a xenograft model following exposure to HSK3486. CONCLUSION: Collectively, our findings revealed that HSK3486 induces oxidative stress, resulting in colorectal cancer cell apoptosis, making it a potential candidate therapeutic strategy for colorectal cancer.

The Causality between Gut Microbiota and Hypertension and Hypertension-related Complications: A Bidirectional Two-Sample Mendelian Randomization Analysis.

BACKGROUND: Recent studies have highlighted a connection between gut microbiota and hypertension, yet the precise nature of this relationship remains unclear. OBJECTIVE: This research aims to analyze the causal link between gut microbiota and hypertension, along with associated complications, utilizing two-sample bidirectional Mendelian randomization (MR). MATERIALS AND METHODS: Summary data from genome-wide association studies (GWAS) meta-analyses, including gut microbiota GWAS data from 24 cohorts, and the latest GWAS data for hypertension-related conditions were acquired. Employing various MR methods, including Inverse-variance weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and Weighted Mode, we investigated the association between gut microbiota and hypertension-related conditions. Sensitivity analyses were conducted for result stability, and reverse MR analysis assessed the potential for reverse causality. RESULTS: The Mendelian randomization analysis involving 199 microbial taxa and four phenotypes identified 46 microbial taxa with potential causal links to hypertension and its complications. Following Bonferroni correction, genus.Victivallis showed a robust causal relationship with hypertension (OR = 1.08, 95% CI = 1.04-1.12, P = 9.82e-5). This suggests an 8% increased risk of hypertension with each unit rise in genus.Victivallis abundance. CONCLUSION: In conclusion, this study establishes a causal connection between gut microbiota and hypertension, along with common associated complications. The findings unveil potential targets and evidence for future hypertension and complication treatment through gut microbiota interventions, offering a novel avenue for therapeutic exploration.

Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury.

BACKGROUND: Sepsis is a severe systemic inflammatory disorder manifested by a dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis and are able to suggest patients' prognoses. At the same time, the specific mechanism of ferritin-induced inflammatory injury remains unclear. METHODS: Hyper-ferritin state during inflammation was performed by injecting ferritin into a mouse model and demonstrated that injection of ferritin could induce a systemic inflammatory response and increase neutrophil extracellular trap (NET) formation.Padi4-/-, Elane-/- and Cybb-/- mice were used for the NETs formation experiment. Western blot, immunofluorescence, ELISA, and flow cytometry examined the changes in NETs, inflammation, and related signaling pathways. RESULTS: Ferritin induces NET formation in a peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), and reactive oxygen species (ROS)-dependent manner, thereby exacerbating the inflammatory response. Mechanistically, ferritin induces the expression of neutrophil macrophage scavenger receptor (MSR), which promotes the formation of NETs. Clinically, high levels of ferritin in patients with severe sepsis correlate with NETs-mediated cytokines storm and are proportional to the severity of sepsis-induced lung injury. CONCLUSIONS: In conclusion, we demonstrated that hyper-ferritin can induce systemic inflammation and increase NET formation in an MSR-dependent manner. This process relies on PAD4, NE, and ROS, further aggravating acute lung injury. In the clinic, high serum ferritin levels are associated with elevated NETs and worse lung injury, which suggests a poor prognosis for patients with sepsis. Our study indicated that targeting NETs or MSR could be a potential treatment to alleviate lung damage and systemic inflammation during sepsis. Video Abstract.

Spatial transcriptomics and single-nucleus RNA sequencing reveal a transcriptomic atlas of adult human spinal cord.

Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and their spatial location remain elusive. Recently, several studies have attempted to define the neuronal types and functional heterogeneity in the spinal cord using single-cell or single-nucleus RNA sequencing in animal models or developing humans. However, molecular evidence of cellular heterogeneity in the adult human spinal cord is limited. Here, we classified spinal cord neurons into 21 subclusters and determined their distribution from nine human donors using single-nucleus RNA sequencing and spatial transcriptomics. Moreover, we compared the human findings with previously published single-nucleus data of the adult mouse spinal cord, which revealed an overall similarity in the neuronal composition of the spinal cord between the two species while simultaneously highlighting some degree of heterogeneity. Additionally, we examined the sex differences in the spinal neuronal subclusters. Several genes, such as SCN10A and HCN1, showed sex differences in motor neurons. Finally, we classified human dorsal root ganglia (DRG) neurons using spatial transcriptomics and explored the putative interactions between DRG and spinal cord neuronal subclusters. In summary, these results illustrate the complexity and diversity of spinal neurons in humans and provide an important resource for future research to explore the molecular mechanisms underlying spinal cord physiology and diseases.