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Nature Oct 2023Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are...
Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are largely elusive. Here we found that chondrocytes produced massive amounts of haemoglobin to form eosin-positive bodies in their cytoplasm. The haemoglobin body (Hedy) is a membraneless condensate characterized by phase separation. Production of haemoglobin in chondrocytes is controlled by hypoxia and is dependent on KLF1 rather than the HIF1/2α pathway. Deletion of haemoglobin in chondrocytes leads to Hedy loss along with severe hypoxia, enhanced glycolysis and extensive cell death in the centre of cartilaginous tissue, which is attributed to the loss of the Hedy-controlled oxygen supply under hypoxic conditions. These results demonstrate an extra-erythrocyte role of haemoglobin in chondrocytes, and uncover a heretofore unrecognized mechanism in which chondrocytes survive a hypoxic environment through Hedy.
Topics: Humans; Cartilage, Articular; Cell Death; Cell Hypoxia; Chondrocytes; Cytoplasm; Eosine Yellowish-(YS); Erythrocytes; Glycolysis; Hemoglobins; Oxygen; Adaptation, Physiological
PubMed: 37794190
DOI: 10.1038/s41586-023-06611-6 -
Cells Aug 2023In all vertebrates, closed blood and open lymph circulatory systems are essential for the delivery of nutrients and oxygen to tissues, waste clearance, and immune...
In all vertebrates, closed blood and open lymph circulatory systems are essential for the delivery of nutrients and oxygen to tissues, waste clearance, and immune function [...].
Topics: Animals; Kinetics; Nutrients; Oxygen; Signal Transduction
PubMed: 37626847
DOI: 10.3390/cells12162038 -
Progress in Retinal and Eye Research Nov 2023Retinal ganglion cells, the neurons that die in glaucoma, are endowed with a high metabolism requiring optimal provision of oxygen and nutrients to sustain their... (Review)
Review
Retinal ganglion cells, the neurons that die in glaucoma, are endowed with a high metabolism requiring optimal provision of oxygen and nutrients to sustain their activity. The timely regulation of blood flow is, therefore, essential to supply firing neurons in active areas with the oxygen and glucose they need for energy. Many glaucoma patients suffer from vascular deficits including reduced blood flow, impaired autoregulation, neurovascular coupling dysfunction, and blood-retina/brain-barrier breakdown. These processes are tightly regulated by a community of cells known as the neurovascular unit comprising neurons, endothelial cells, pericytes, Müller cells, astrocytes, and microglia. In this review, the neurovascular unit takes center stage as we examine the ability of its members to regulate neurovascular interactions and how their function might be altered during glaucomatous stress. Pericytes receive special attention based on recent data demonstrating their key role in the regulation of neurovascular coupling in physiological and pathological conditions. Of particular interest is the discovery and characterization of tunneling nanotubes, thin actin-based conduits that connect distal pericytes, which play essential roles in the complex spatial and temporal distribution of blood within the retinal capillary network. We discuss cellular and molecular mechanisms of neurovascular interactions and their pathophysiological implications, while highlighting opportunities to develop strategies for vascular protection and regeneration to improve functional outcomes in glaucoma.
Topics: Humans; Endothelial Cells; Brain; Nanotubes; Oxygen
PubMed: 37778617
DOI: 10.1016/j.preteyeres.2023.101217 -
Nature Aug 2023The human gut microbiota has gained interest as an environmental factor that may contribute to health or disease. The development of next-generation probiotics is a...
The human gut microbiota has gained interest as an environmental factor that may contribute to health or disease. The development of next-generation probiotics is a promising strategy to modulate the gut microbiota and improve human health; however, several key candidate next-generation probiotics are strictly anaerobic and may require synergy with other bacteria for optimal growth. Faecalibacterium prausnitzii is a highly prevalent and abundant human gut bacterium associated with human health, but it has not yet been developed into probiotic formulations. Here we describe the co-isolation of F. prausnitzii and Desulfovibrio piger, a sulfate-reducing bacterium, and their cross-feeding for growth and butyrate production. To produce a next-generation probiotic formulation, we adapted F. prausnitzii to tolerate oxygen exposure, and, in proof-of-concept studies, we demonstrate that the symbiotic product is tolerated by mice and humans (ClinicalTrials.gov identifier: NCT03728868 ) and is detected in the human gut in a subset of study participants. Our study describes a technology for the production of next-generation probiotics based on the adaptation of strictly anaerobic bacteria to tolerate oxygen exposures without a reduction in potential beneficial properties. Our technology may be used for the development of other strictly anaerobic strains as next-generation probiotics.
Topics: Animals; Humans; Mice; Butyrates; Gastrointestinal Microbiome; Oxygen; Probiotics; Aerobiosis; Faecalibacterium prausnitzii; Symbiosis; Biotechnology
PubMed: 37532933
DOI: 10.1038/s41586-023-06378-w -
Intensive Care Medicine Sep 2023The cerebral oxygen cascade includes three key stages: (a) convective oxygen delivery representing the bulk flow of oxygen to the cerebral vascular bed; (b) diffusion of... (Review)
Review
The cerebral oxygen cascade includes three key stages: (a) convective oxygen delivery representing the bulk flow of oxygen to the cerebral vascular bed; (b) diffusion of oxygen from the blood into brain tissue; and (c) cellular utilisation of oxygen for aerobic metabolism. All three stages may become dysfunctional after resuscitation from cardiac arrest and contribute to hypoxic-ischaemic brain injury (HIBI). Improving convective cerebral oxygen delivery by optimising cerebral blood flow has been widely investigated as a strategy to mitigate HIBI. However, clinical trials aimed at optimising convective oxygen delivery have yielded neutral results. Advances in the understanding of HIBI pathophysiology suggest that impairments in the stages of the oxygen cascade pertaining to oxygen diffusion and cellular utilisation of oxygen should also be considered in identifying therapeutic strategies for the clinical management of HIBI patients. Culprit mechanisms for these impairments may include a widening of the diffusion barrier due to peri-vascular oedema and mitochondrial dysfunction. An integrated approach encompassing both intra-parenchymal and non-invasive neuromonitoring techniques may aid in detecting pathophysiologic changes in the oxygen cascade and enable patient-specific management aimed at reducing the severity of HIBI.
Topics: Humans; Oxygen; Brain; Hypoxia-Ischemia, Brain; Heart Arrest; Cerebrovascular Circulation; Brain Injuries
PubMed: 37507572
DOI: 10.1007/s00134-023-07165-x -
Critical Care (London, England) Jun 2023To describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation.
DESIGN
Systematic review with an individual data meta-analysis.
SETTING
Observational and interventional (before/after) studies published up to August 22nd, 2022, were considered for inclusion. We investigated the effects of low tidal volume Vt < 8 ml/Kg of IBW versus Vt > = 8 ml/Kg of IBW, positive end-expiratory pressure (PEEP) < or > = 5 cmHO and protective ventilation (association of both) on relevant clinical outcomes.
POPULATION
Patients with acute brain injury (trauma or haemorrhagic stroke) with invasive mechanical ventilation for ≥ 24 h.
MAIN OUTCOME MEASURES
The primary outcome was mortality at 28 days or in-hospital mortality. Secondary outcomes were the incidence of acute respiratory distress syndrome (ARDS), the duration of mechanical ventilation and the partial pressure of oxygen (PaO)/fraction of inspired oxygen (FiO) ratio.
RESULTS
The meta-analysis included eight studies with a total of 5639 patients. There was no difference in mortality between low and high tidal volume [Odds Ratio, OR 0.88 (95%Confidence Interval, CI 0.74 to 1.05), p = 0.16, I = 20%], low and moderate to high PEEP [OR 0.8 (95% CI 0.59 to 1.07), p = 0.13, I = 80%] or protective and non-protective ventilation [OR 1.03 (95% CI 0.93 to 1.15), p = 0.6, I = 11]. Low tidal volume [OR 0.74 (95% CI 0.45 to 1.21, p = 0.23, I = 88%], moderate PEEP [OR 0.98 (95% CI 0.76 to 1.26), p = 0.9, I = 21%] or protective ventilation [OR 1.22 (95% CI 0.94 to 1.58), p = 0.13, I = 22%] did not affect the incidence of acute respiratory distress syndrome. Protective ventilation improved the PaO/FiO ratio in the first five days of mechanical ventilation (p < 0.01).
CONCLUSIONS
Low tidal volume, moderate to high PEEP, or protective ventilation were not associated with mortality and lower incidence of ARDS in patients with acute brain injury undergoing invasive mechanical ventilation. However, protective ventilation improved oxygenation and could be safely considered in this setting. The exact role of ventilatory management on the outcome of patients with a severe brain injury needs to be more accurately delineated.
Topics: Humans; Respiration, Artificial; Tidal Volume; Respiratory Distress Syndrome; Oxygen; Brain Injuries
PubMed: 37280579
DOI: 10.1186/s13054-023-04509-3 -
The Journal of Biological Chemistry Sep 2023Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through...
Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through evolution. The promiscuous nature of ferredoxins as electron donors enables them to participate in many metabolic processes including steroid, heme, vitamin D, and Fe-S cluster biosynthesis in different organisms. However, the unique natural function(s) of each of the two human ferredoxins (FDX1 and FDX2) are still poorly characterized. We recently reported that FDX1 is both a crucial regulator of copper ionophore-induced cell death and serves as an upstream regulator of cellular protein lipoylation, a mitochondrial lipid-based post-translational modification naturally occurring on four mitochondrial enzymes that are crucial for TCA cycle function. Here we show that FDX1 directly regulates protein lipoylation by binding the lipoyl synthase (LIAS) enzyme promoting its functional binding to the lipoyl carrier protein GCSH and not through indirect regulation of cellular Fe-S cluster biosynthesis. Metabolite profiling revealed that the predominant cellular metabolic outcome of FDX1 loss of function is manifested through the regulation of the four lipoylation-dependent enzymes ultimately resulting in loss of cellular respiration and sensitivity to mild glucose starvation. Transcriptional profiling established that FDX1 loss-of-function results in the induction of both compensatory metabolism-related genes and the integrated stress response, consistent with our findings that FDX1 loss-of-function is conditionally lethal. Together, our findings establish that FDX1 directly engages with LIAS, promoting its role in cellular protein lipoylation, a process essential in maintaining cell viability under low glucose conditions.
Topics: Humans; Ferredoxins; Lipoylation; Protein Binding; Cell Respiration; Cell Proliferation; Metabolome; Sulfurtransferases
PubMed: 37453661
DOI: 10.1016/j.jbc.2023.105046 -
Current Opinion in Microbiology Apr 2024Cyanobacteria evolved the oxygenic photosynthesis to generate organic matter from CO and sunlight, and they were responsible for the production of oxygen in the Earth's... (Review)
Review
Cyanobacteria evolved the oxygenic photosynthesis to generate organic matter from CO and sunlight, and they were responsible for the production of oxygen in the Earth's atmosphere. This made them a model for photosynthetic organisms, since they are easier to study than higher plants. Early studies suggested that only a minority among cyanobacteria might assimilate organic compounds, being considered mostly autotrophic for decades. However, compelling evidence from marine and freshwater cyanobacteria, including toxic strains, in the laboratory and in the field, has been obtained in the last decades: by using physiological and omics approaches, mixotrophy has been found to be a more widespread feature than initially believed. Furthermore, dominant clades of marine cyanobacteria can take up organic compounds, and mixotrophy is critical for their survival in deep waters with very low light. Hence, mixotrophy seems to be an essential trait in the metabolism of most cyanobacteria, which can be exploited for biotechnological purposes.
Topics: Cyanobacteria; Photosynthesis; Atmosphere; Oxygen
PubMed: 38325247
DOI: 10.1016/j.mib.2024.102432 -
NeuroImage Aug 2023This article provides an overview of MRI methods exploiting magnetic susceptibility properties of blood to assess cerebral oxygen metabolism, including the tissue oxygen... (Review)
Review
This article provides an overview of MRI methods exploiting magnetic susceptibility properties of blood to assess cerebral oxygen metabolism, including the tissue oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO). The first section is devoted to describing blood magnetic susceptibility and its effect on the MRI signal. Blood circulating in the vasculature can have diamagnetic (oxyhemoglobin) or paramagnetic properties (deoxyhemoglobin). The overall balance between oxygenated and deoxygenated hemoglobin determines the induced magnetic field which, in turn, modulates the transverse relaxation decay of the MRI signal via additional phase accumulation. The following sections of this review then illustrate the principles underpinning susceptibility-based techniques for quantifying OEF and CMRO. Here, it is detailed whether these techniques provide global (OxFlow) or local (Quantitative Susceptibility Mapping - QSM, calibrated BOLD - cBOLD, quantitative BOLD - qBOLD, QSM+qBOLD) measurements of OEF or CMRO, and what signal components (magnitude or phase) and tissue pools they consider (intravascular or extravascular). Validations studies and potential limitations of each method are also described. The latter include (but are not limited to) challenges in the experimental setup, the accuracy of signal modeling, and assumptions on the measured signal. The last section outlines the clinical uses of these techniques in healthy aging and neurodegenerative diseases and contextualizes these reports relative to results from gold-standard PET.
Topics: Humans; Brain; Magnetic Resonance Imaging; Oxygen; Oxygen Consumption; Cerebrovascular Circulation
PubMed: 37230206
DOI: 10.1016/j.neuroimage.2023.120189