-
Journal of Nanobiotechnology Jun 2024Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI....
Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.
Topics: Animals; Acute Lung Injury; Sepsis; Extracellular Vesicles; MicroRNAs; Mice; Nanoparticles; Macrophages; Mice, Inbred C57BL; Humans; Male; Lipopolysaccharides; Neutrophils; Oxidative Stress; Lung; Biomimetic Materials; Multiomics
PubMed: 38910259
DOI: 10.1186/s12951-024-02597-z -
The Journal of Heart and Lung... Jun 2024The age profile of organ donors and patients on lung transplantation (LT) waiting lists have changed over time. In Europe, the donor population has aged much more...
BACKGROUND
The age profile of organ donors and patients on lung transplantation (LT) waiting lists have changed over time. In Europe, the donor population has aged much more rapidly than the recipient population, making allocation decisions on lungs from older donors common. In this study we assessed the impact of donor and recipient age discrepancy on LT outcomes in the UK and France.
METHODS
A retrospective analysis of all adult single or bilateral LT in France and the UK between 2010 and 2021. Recipients were stratified into 3 age groups: young (≤ 30 years), middle-aged (30 to 60) and older (≥60). Their donors were also stratified into 2 groups <60, ≥ 60. Primary graft dysfunction (PGD) rates and recipient survival was compared between matched and mismatched donor and recipient age groups. Propensity matching was employed to minimize covariate imbalances and to improve the internal validity of our results.
RESULTS
Our study cohort was 4,696 lung transplant recipients (LTRs). In young and older LTRs, there was no significant difference in 1 and 5-years post-transplant survival dependent on the age category of the donor. Young LTRs who received older donor grafts had a higher risk of severe grade 3 PGD.
CONCLUSION
Our findings show that clinically usable organs from older donors can be utilized safely in LT, even for younger recipients. Further research is needed to assess if the higher rate of PGD3 associated with use of older donors has an effect on long-term outcomes.
PubMed: 38909711
DOI: 10.1016/j.healun.2024.06.008 -
Maturitas Jun 2024Worsening of sleep quality during menopause is well recognized. However, the underlying hormonal regulation is insufficiently described. In this study, we evaluated...
OBJECTIVE
Worsening of sleep quality during menopause is well recognized. However, the underlying hormonal regulation is insufficiently described. In this study, we evaluated associations between sleep and cortisol levels.
STUDY DESIGN
Seventeen perimenopausal and 18 postmenopausal women were enrolled in a three-night sleep study. Diurnal blood sampling was performed during the third night and the following day.
MAIN OUTCOME MEASURES
Self-reported insomnia and sleepiness were evaluated with the Basic Nordic Sleep Questionnaire and sleep architecture with all-night polysomnography. Diurnal cortisol samples were collected at 20-min intervals. Correlation analyses and generalized linear models adjusted by age, body mass index, vasomotor symptoms and depressive symptoms were conducted.
RESULTS
In correlation analyses, self-reported insomnia and sleepiness were not associated with cortisol levels. Lower sleep efficiency, slow-wave sleep and stage 1 percentages, number of slow-wave sleep and of rapid-eye-movement (REM) periods, longer slow-wave sleep latency and higher wake after sleep onset percentage were associated with higher cortisol levels (all p < 0.05). Further, lower slow-wave sleep percentage and longer slow-wave sleep latency correlated with steeper daytime cortisol slope (i.e. day cortisol decrease, both p < 0.05). In adjusted generalized linear models, lower sleep efficiency and number of rapid-eye-movement periods as well as higher wake after sleep onset percentage correlated with higher cortisol levels; lower slow-wave sleep percentage correlated with higher cortisol awakening response.
CONCLUSIONS
Worse sleep architecture but not worse self-reported insomnia and sleepiness was associated with higher cortisol levels. This is important for understanding sleep in women, especially during the menopausal period.
PubMed: 38909441
DOI: 10.1016/j.maturitas.2024.108053 -
Immunity & Ageing : I & A Jun 2024Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population...
Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell-cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.
PubMed: 38909272
DOI: 10.1186/s12979-024-00446-z -
Cell & Bioscience Jun 2024Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there... (Review)
Review
Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there is no direct lung damage, severe brain injury can enhance sympathetic tones on blood vessels and vascular resistance, resulting in neurogenic pulmonary edema. Conversely, lung damage can worsen brain damage by dysregulating immunity. These findings suggest the importance of brain-lung axis interactions in TBI. However, little research has been conducted on the topic. An advanced disease model using stem cell technology may be an alternative for investigating the brain and lungs simultaneously but separately, as they can be potential candidates for improving the clinical outcomes of TBI.In this review, we describe the importance of brain-lung axis interactions in TBI by focusing on the concepts and reproducibility of brain and lung organoids in vitro. We also summarize recent research using pluripotent stem cell-derived brain organoids and their preclinical applications in various brain disease conditions and explore how they mimic the brain-lung axis. Reviewing the current status and discussing the limitations and potential perspectives in organoid research may offer a better understanding of pathophysiological interactions between the brain and lung after TBI.
PubMed: 38909262
DOI: 10.1186/s13578-024-01252-2 -
BMC Geriatrics Jun 2024The accelerated growth of older individuals worldwide has increased the number of patients presenting with fragility hip fractures. Having a hip fracture can cause...
BACKGROUND
The accelerated growth of older individuals worldwide has increased the number of patients presenting with fragility hip fractures. Having a hip fracture can cause excess mortality, and patients with hip fracture have a higher risk of death than those without hip fracture. Most studies have treated hip fracture as a single, homogeneous condition, but hip fracture includes two major anatomic types: intertrochanteric fracture and femoral neck fracture. Few studies have specifically evaluated 1-year mortality risk in older individuals with femoral intertrochanteric fracture. The aim of this study was to evaluate 1-year mortality and factors associated with mortality in older individuals with femoral intertrochanteric fracture.
METHODS
A retrospective review was conducted of 563 patients ≥ 65 years old who underwent surgery for femoral intertrochanteric fractures at our institution between January 2010 and August 2018. Patient demographics, comorbidities, and treatment were collected by retrospective chart review. Age, sex, Body Mass Index (BMI), American Society of Anesthesiologists (ASA) classification, Charlson comorbidity index (CCI), Arbeitsgemeinschaft Für Osteosynthesefragen (AO) fracture classification, haemoglobin value at admission, time to surgery, operation time, and intraoperative blood loss were risk factors to be tested. Multivariable logistic regression was used to evaluate associations between variables and death.
RESULTS
Among the 563 patients, 49 died within 1 year after surgery, and the 1-year mortality rate was 8.7%. Multivariate analysis identified age > 80 years (OR = 4.038, P = 0.011), haemoglobin < 100 g/l (OR = 2.732, P = 0.002), ASA score ≥ 3 (OR = 2.551, P = 0.005), CCI ≥ 3 (OR = 18.412, P = 0.018) and time to surgery > 14 d (OR = 3.907, P = 0.030) as independent risk factors for 1-year mortality. Comorbidities such as myocardial infarction and chronic pulmonary disease were associated with 1-year mortality after adjusting for age > 80 years and time to surgery > 14 days.
CONCLUSIONS
Patients over 80 years old with haemoglobin < 100 g/l, ASA score ≥ 3, CCI ≥ 3, and multiple comorbidities, especially myocardial infarction and chronic pulmonary disease before surgery, are at a higher risk of 1-year mortality. Doctors should pay more attention to these vulnerable patients, and a surgical delay greater than 14 days should be avoided.
Topics: Humans; Male; Female; Aged; Retrospective Studies; Hip Fractures; China; Aged, 80 and over; Risk Factors; Tertiary Care Centers; Risk Assessment
PubMed: 38909190
DOI: 10.1186/s12877-024-05159-y -
Scientific Reports Jun 2024Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites...
Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 μM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.
Topics: Succinic Acid; Receptors, G-Protein-Coupled; Humans; Idiopathic Pulmonary Fibrosis; Animals; Male; Mice; Female; Middle Aged; Prognosis; Aged; Disease Models, Animal; Biomarkers; Fibroblasts; Citric Acid Cycle
PubMed: 38909094
DOI: 10.1038/s41598-024-64844-5 -
Scientific Reports Jun 2024Metabolic syndrome (MetS) poses a significant public health challenge globally, including in Ethiopia, with risks for both mothers and children. Unfortunately, there is...
Metabolic syndrome (MetS) poses a significant public health challenge globally, including in Ethiopia, with risks for both mothers and children. Unfortunately, there is limited data on MetS in pregnant Ethiopian women. This study aims to evaluate the prevalence and factors associated with MetS in this population. A cross-sectional study was conducted using a systematic random sampling technique. Data were collected through face-to-face interviews using a structured questionnaire adapted from the World Health Organization Steps Survey Tool for Non-communicable Diseases. About five ml of fasting peripheral blood samples were collected from each participant. The Beckman Coulter DXC 700 AU clinical chemistry analyzer was employed for lipid profile and glucose analysis. Subsequently, data were inputted into Epi Data and later exported to SPSS Version 20 for further analysis. Bivariable and multivariable binary logistic regression analyses were carried out, with a predefined level of statistical significance at p < 0.05. A total of 318 pregnant women were included in this study. The prevalence of MetS was 13.2% (95% CI: 9.7, 17.0) based on the American Heart Association/National Heart Lung and Blood Institute definition. The most prevalent components of MetS were elevated triglyceride levels, reduced high-density lipoprotein levels, and elevated blood pressure. Unhealthy sleep duration (AOR = 5.6, 95% CI (2.4, 13.1), p < 0.001), high daily salt intake (AOR = 4.2, 95% CI (1.8, 9.5), p = 0.001), and alcohol consumption [AOR = 4.2, 95% CI (1.6, 10.9), p = 0.003] were significantly associated with MetS. The study reported a high prevalence of MetS in pregnant Ethiopian women. Factors including alcohol, high salt intake, and sleep disturbances were associated with MetS. Policymakers might utilize this data to create targeted interventions and public health policies for MetS among pregnant women, focusing on nutrition, sleep, and alcohol consumption during pregnancy to safeguard maternal and fetal health.
Topics: Humans; Female; Metabolic Syndrome; Ethiopia; Pregnancy; Adult; Cross-Sectional Studies; Prevalence; Risk Factors; Young Adult; Pregnancy Complications
PubMed: 38909078
DOI: 10.1038/s41598-024-65107-z -
Cell Death & Disease Jun 2024The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell...
The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.
Topics: Humans; Endocytosis; Apoptosis; Animals; Fas Ligand Protein; fas Receptor; Mice; Cell Line, Tumor; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Xenograft Model Antitumor Assays; Glioblastoma
PubMed: 38909035
DOI: 10.1038/s41419-024-06822-3 -
Nature Communications Jun 2024During primary varicella zoster virus (VZV) infection, infected lymphocytes drive primary viremia, causing systemic dissemination throughout the host, including the...
During primary varicella zoster virus (VZV) infection, infected lymphocytes drive primary viremia, causing systemic dissemination throughout the host, including the skin. This results in cytokine expression, including interferons (IFNs), which partly limit infection. VZV also spreads from skin keratinocytes to lymphocytes prior to secondary viremia. It is not clear how VZV achieves this while evading the cytokine response. Here, we show that VZV glycoprotein C (gC) binds IFN-γ and modifies its activity, increasing the expression of a subset of IFN-stimulated genes (ISGs), including intercellular adhesion molecule 1 (ICAM1), chemokines and immunomodulatory genes. The higher ICAM1 protein level at the plasma membrane of keratinocytes facilitates lymphocyte function-associated antigen 1-dependent T cell adhesion and expression of gC during infection increases VZV spread to peripheral blood mononuclear cells. This constitutes the discovery of a strategy to modulate IFN-γ activity, upregulating a subset of ISGs, promoting enhanced lymphocyte adhesion and virus spread.
Topics: Humans; Interferon-gamma; Cell Adhesion; T-Lymphocytes; Intercellular Adhesion Molecule-1; Keratinocytes; Herpesvirus 3, Human; Varicella Zoster Virus Infection; Leukocytes, Mononuclear; Viral Envelope Proteins; Lymphocyte Function-Associated Antigen-1
PubMed: 38909022
DOI: 10.1038/s41467-024-49657-4