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Scientific Reports Sep 2023Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative pluripotent stem cells present in the bone marrow, peripheral blood, and organ...
Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative pluripotent stem cells present in the bone marrow, peripheral blood, and organ connective tissues. We assessed the homing and therapeutic effects of systemically administered nafimestrocel, a clinical-grade human Muse cell-based product, without immunosuppressants in a neonatal hypoxic-ischemic (HI) rat model. HI injury was induced on postnatal day 7 (P7) and was confirmed by T2-weighted magnetic resonance imaging on P10. HI rats received a single dose nafimestrocel (1 × 10 cells/body) or Hank's balanced salt solution (vehicle group) intravenously at either three days (on P10; M3 group) or seven days (on P14; M7 group) after HI insult. Radioisotope experiment demonstrated the homing of chromium-51-labeled nafimestrocel to the both cerebral hemispheres. The cylinder test (M3 and M7 groups) and open-field test (M7 group) showed significant amelioration of paralysis and hyperactivity at five weeks of age compared with those in the vehicle group. Nafimestrocel did not cause adverse events such as death or pathological changes in the lung at ten weeks in the both groups. Nafimestrocel attenuated the production of tumor necrosis factor-α and inducible nitric oxide synthase from activated cultured microglia in vitro. These results demonstrate the potential therapeutic benefits and safety of nafimestrocel.
Topics: Humans; Animals; Rats; Animals, Newborn; Alprostadil; Hypoxia-Ischemia, Brain; Hypoxia; Excipients; Brain Injuries
PubMed: 37696826
DOI: 10.1038/s41598-023-41026-3 -
Annals of the American Thoracic Society Dec 2023
Topics: Humans; Lung Diseases, Interstitial; Fibrosis; Hypoxia
PubMed: 38038603
DOI: 10.1513/AnnalsATS.202309-840ED -
International Journal of Medical... 2023Severe hypoxia can induce a range of systemic disorders; however, surprising resilience can be obtained through sublethal adaptation to hypoxia, a process termed as... (Review)
Review
Severe hypoxia can induce a range of systemic disorders; however, surprising resilience can be obtained through sublethal adaptation to hypoxia, a process termed as hypoxic conditioning. A particular form of this strategy, known as intermittent hypoxia conditioning hormesis, alternates exposure to hypoxic and normoxic conditions, facilitating adaptation to reduced oxygen availability. This technique, originally employed in sports and high-altitude medicine, has shown promise in multiple pathologies when applied with calibrated mild to moderate hypoxia and appropriate hypoxic cycles. Recent studies have extensively investigated the protective role of intermittent hypoxia conditioning and its underlying mechanisms using animal models, demonstrating its potential in organ protection. This involves a range of processes such as reduction of oxidative stress, inflammation, and apoptosis, along with enhancement of hypoxic gene expression, among others. Given that intermittent hypoxia conditioning fosters beneficial physiological responses across multiple organs and systems, this review presents a comprehensive analysis of existing studies on intermittent hypoxia and its potential advantages in various organs. It aims to draw attention to the possibility of clinically applying intermittent hypoxia conditioning as a multi-organ protective strategy. This review comprehensively discusses the protective effects of intermittent hypoxia across multiple systems, outlines potential procedures for implementing intermittent hypoxia, and provides a brief overview of the potential protective mechanisms of intermittent hypoxia.
Topics: Animals; Hypoxia; Oxygen; Oxidative Stress
PubMed: 37859700
DOI: 10.7150/ijms.86622 -
Resuscitation Aug 2023Prognostication of comatose patients after cardiac arrest aims to identify patients with a large probability of favourable or unfavouble outcome, usually within the... (Review)
Review
Prognostication of comatose patients after cardiac arrest aims to identify patients with a large probability of favourable or unfavouble outcome, usually within the first week after the event. Electroencephalography (EEG) is a technique that is increasingly used for this purpose and has many advantages, such as its non-invasive nature and the possibility to monitor the evolution of brain function over time. At the same time, use of EEG in a critical care environment faces a number of challenges. This narrative review describes the current role and future applications of EEG for outcome prediction of comatose patients with postanoxic encephalopathy.
Topics: Humans; Coma; Prognosis; Electroencephalography; Hypoxia-Ischemia, Brain; Brain Injuries; Intensive Care Units
PubMed: 37419237
DOI: 10.1016/j.resuscitation.2023.109900 -
The European Respiratory Journal Jul 2023https://bit.ly/3Wnzpik
https://bit.ly/3Wnzpik
Topics: Humans; Hypertension, Pulmonary; Hypoxia; Respiration Disorders; Pulmonary Disease, Chronic Obstructive; Oxygen
PubMed: 37414421
DOI: 10.1183/13993003.00463-2023 -
Biomolecules Oct 2023Hypoxia-induced retinal neovascularization is a leading cause of blindness worldwide. Oxygen-induced retinopathy (OIR) mouse, a well-established angiogenesis model, has...
Hypoxia-induced retinal neovascularization is a leading cause of blindness worldwide. Oxygen-induced retinopathy (OIR) mouse, a well-established angiogenesis model, has been extensively used to evaluate the effect of anti-angiogenic agents through intravitreal injection. Here, we serendipitously found that the needles used for intravitreal injection caused an unexpected "anti-angiogenic" effect in the OIR mice. To evaluate the effects of various intravitreal puncture sizes on retinal neovascularization and explore the potential underlying mechanism, intravitreal punctures using 0.5 mm (25 G), 0.3 mm (30 G), or 0.21 mm (33 G) needles were performed in OIR mice. Compared with 0.3 mm and 0.21 mm puncture, the 0.5 mm puncture remarkably suppressed the formation of pathological angiogenesis, inhibited vascular leakage, and remodeled the retinal vasculature. Mechanistically, the 0.5 mm puncture induced a substantial reduction in intraocular pressure (IOP), leading to an improvement in oxygen partial pressure (pO) and significant reduction in Hif1a expression, resulting in resolution of angiogenic and inflammatory responses. Furthermore, IOP-lowering drugs, Travatan or Azarga, also promoted the alleviation of hypoxia and exhibited a potent anti-angiogenesis efficacy. Our study revealed an acute and significant reduction in IOP caused by a large puncture, which could remarkably suppress HIF-1α-mediated retinal neovascularization, indicating that lowering IOP may be a promising therapeutic avenue for treating retinal neovascular diseases.
Topics: Animals; Mice; Retinal Neovascularization; Intraocular Pressure; Neovascularization, Pathologic; Retinal Diseases; Oxygen; Hypoxia; Angiogenesis Inhibitors; Mice, Inbred C57BL
PubMed: 37892214
DOI: 10.3390/biom13101532 -
Frontiers in Immunology 2023Given the increasing incidence of pancreatic cancer and the low survival rate, the exploration of the complex tumor microenvironment and the development of novel...
Given the increasing incidence of pancreatic cancer and the low survival rate, the exploration of the complex tumor microenvironment and the development of novel treatment options is urgent. NK cells, known for their cytotoxic abilities and modulation of other immune cells, are vital in recognizing and killing cancer cells. However, hypoxic conditions in the tumor microenvironment have been found to impair NK cell functionality and contribute to tumor immune escape. Therefore, we aimed to uncover the mechanism through which hypoxia mediates the immune escape of pancreatic cancer cells, focusing on the influence of miR-1275/AXIN2 on NK cells. Using a combination of GEO dataset screening, Tumor Immune Estimation Resource 2.0 immunoscore screening, and the Cancer Genome Atlas data, we identified a correlation between miR-1275 and NK cells. The down-regulation of miR-1275 was associated with decreased NK cell activity and survival in patients with pancreatic cancer. Pathway analysis further linked miR-1275 expression with the hypoxic HIF1A pathway. experiments were conducted using the NK-92 cell, revealing that hypoxia significantly reduced miR-1275 expression and correspondingly decreased the cell-killing ability of NK cells. Upregulation of miR-1275 increased perforin, IFN-γ and TNF-α expression levels and enhanced NK cell cytotoxicity. Additionally, miR-1275 was found to bind to and inhibit AXIN2 expression, which when overexpressed, partially alleviated the promotive effect of upregulated miR-1275 on NK-92 cell killing ability. In conclusion, this research underscores the critical role of the miR-1275/AXIN2 axis in hypoxia-mediated immune escape in pancreatic cancer, thus opening new potential avenues for treatment strategies.
Topics: Humans; Killer Cells, Natural; Pancreatic Neoplasms; Hypoxia; MicroRNAs; Tumor Microenvironment; Axin Protein
PubMed: 38035113
DOI: 10.3389/fimmu.2023.1271603 -
Pediatric Critical Care Medicine : a... Oct 2023Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to... (Observational Study)
Observational Study
OBJECTIVES
Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies.
DESIGN
Multicenter observational cohort study.
SETTING
Thirteen PICUs in the United States.
PATIENTS
Patients admitted with suspected infections to the PICU between 2012 and 2018.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%-60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS.
CONCLUSIONS
We derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis.
Topics: Child; Humans; Multiple Organ Failure; Clinical Relevance; Reproducibility of Results; Sepsis; Shock, Septic; Phenotype; Brain Diseases; Hypoxia
PubMed: 37272946
DOI: 10.1097/PCC.0000000000003292 -
PloS One 2023Previous studies have shown that the hypoxia microenvironment significantly impacted tumor progression. However, the clinical prognostic value of hypoxia-related risk...
BACKGROUND
Previous studies have shown that the hypoxia microenvironment significantly impacted tumor progression. However, the clinical prognostic value of hypoxia-related risk signatures and their effects on the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains hazy. This study aimed to conduct novel hypoxia-related prognostic signatures and improve HCC prognosis and treatment.
METHODS
Differentially expressed hypoxia-related genes (HGs) were identified with the gene set enrichment analysis (GSEA). Univariate Cox regression was utilized to generate the tumor hypoxia-related prognostic signature, which consists of 3 HGs, based on the least absolute shrinkage and selection operator (LASSO) algorithm. Then the risk score for each patient was performed. The prognostic signature's independent prognostic usefulness was confirmed, and systematic analyses were done on the relationships between the prognostic signature and immune cell infiltration, somatic cell mutation, medication sensitivity, and putative immunological checkpoints.
RESULTS
A prognostic risk model of four HGs (FDPS, SRM, and NDRG1) was constructed and validated in the training, testing, and validation datasets. To determine the model's performance in patients with HCC, Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves analysis was implemented. According to immune infiltration analysis, the high-risk group had a significant infiltration of CD4+ T cells, M0 macrophages, and dendritic cells (DCs) than those of the low-risk subtype. In addition, the presence of TP53 mutations in the high-risk group was higher, in which LY317615, PF-562271, Pyrimethamine, and Sunitinib were more sensitive. The CD86, LAIR1, and LGALS9 expression were upregulated in the high-risk subtype.
CONCLUSIONS
The hypoxia-related risk signature is a reliable predictive model for better clinical management of HCC patients and offers clinicians a holistic viewpoint when determining the diagnosis and course of HCC treatment.
Topics: Humans; Female; Prognosis; Carcinoma, Hepatocellular; Liver Neoplasms; Genes, Regulator; Hypoxia; Fetal Hypoxia; Tumor Microenvironment
PubMed: 37406019
DOI: 10.1371/journal.pone.0288013 -
Pharmacological Research Nov 2023Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However,...
Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However, the specific mechanism underlying hypoxia in BCSC induction is not completely understood. Herein, we provide evidence that a novel hypoxia-specific circSTT3A is significantly upregulated in clinical breast cancer (BC) tissues, and is closely related to the clinical stage and poor prognosis of patients with BC. The study revealed that hypoxia-inducible factor 1 alpha (HIF1α)-regulated circSTT3A has a remarkable effect on mammosphere formation in breast cancer cells. Mechanistically, circSTT3A directly interacts with nucleotide-binding domain of heat shock protein 70 (HSP70), thereby facilitating the recruitment of phosphoglycerate kinase 1 (PGK1) via its substrate-binding domain, which reduces the ubiquitination and increases the stability of PGK1. The enhanced levels of PGK1 catalyze 1,3-diphosphoglycerate (1,3-BPG) into 3-phosphoglycerate (3-PG) leading to 3-PG accumulation and increased serine synthesis, S-adenosylmethionine (SAM) accumulation, and trimethylation of histone H3 lysine 4 (H3K4me3). The activation of the H3K4me3 contributes to BCSCs by increasing the transcriptional level of stemness-related factors. Especially, our work reveals that either loss of circSTT3A or PGK1 substantially suppresses tumor initiation and tumor growth, which dramatically increases the sensitivity of tumors to doxorubicin (DOX) in mice. Injection of PGK1-silenced spheroids with 3-PG can significantly reverse tumor initiation and growth in mice, thereby increasing tumor resistance to DOX. In conclusion, our study sheds light on the functional role of hypoxia in the maintenance of BCSCs via circSTT3A/HSP70/PGK1-mediated serine synthesis, which provides new insights into metabolic reprogramming, tumor initiation and growth. Our findings suggest that targeting circSTT3A alone or in combination with chemotherapy has potential clinical value for BC management.
Topics: Humans; Mice; Animals; Female; Breast Neoplasms; Histones; Hypoxia; Cell Transformation, Neoplastic; Neoplastic Stem Cells; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37865128
DOI: 10.1016/j.phrs.2023.106964