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Circulation Research May 2024During myocardial ischemia/reperfusion (I/R) injury, high levels of matrix Ca and reactive oxygen species (ROS) induce the opening of the mitochondrial permeability...
BACKGROUND
During myocardial ischemia/reperfusion (I/R) injury, high levels of matrix Ca and reactive oxygen species (ROS) induce the opening of the mitochondrial permeability transition pore (mPTP), which causes mitochondrial dysfunction and ultimately necrotic death. However, the mechanisms of how these triggers individually or cooperatively open the pore have yet to be determined.
METHODS
Here, we use a combination of isolated mitochondrial assays and in vivo I/R surgery in mice. We challenged isolated liver and heart mitochondria with Ca, ROS, and Fe to induce mitochondrial swelling. Using inhibitors of the mPTP (cyclosporine A or ADP) lipid peroxidation (ferrostatin-1, MitoQ), we determined how the triggers elicit mitochondrial damage. Additionally, we used the combination of inhibitors during I/R injury in mice to determine if dual inhibition of these pathways is additivity protective.
RESULTS
In the absence of Ca, we determined that ROS fails to trigger mPTP opening. Instead, high levels of ROS induce mitochondrial dysfunction and rupture independently of the mPTP through lipid peroxidation. As expected, Ca in the absence of ROS induces mPTP-dependent mitochondrial swelling. Subtoxic levels of ROS and Ca synergize to induce mPTP opening. Furthermore, this synergistic form of Ca- and ROS-induced mPTP opening persists in the absence of CypD (cyclophilin D), suggesting the existence of a CypD-independent mechanism for ROS sensitization of the mPTP. These ex vivo findings suggest that mitochondrial dysfunction may be achieved by multiple means during I/R injury. We determined that dual inhibition of the mPTP and lipid peroxidation is significantly more protective against I/R injury than individually targeting either pathway alone.
CONCLUSIONS
In the present study, we have investigated the relationship between Ca and ROS, and how they individually or synergistically induce mitochondrial swelling. Our findings suggest that Ca mediates mitochondrial damage through the opening of the mPTP, although ROS mediates its damaging effects through lipid peroxidation. However, subtoxic levels both Ca and ROS can induce mPTP-mediated mitochondrial damage. Targeting both of these triggers to preserve mitochondria viability unveils a highly effective therapeutic approach for mitigating I/R injury.
Topics: Animals; Lipid Peroxidation; Mitochondrial Permeability Transition Pore; Reactive Oxygen Species; Mice; Mitochondria, Heart; Male; Myocardial Reperfusion Injury; Mice, Inbred C57BL; Mitochondrial Membrane Transport Proteins; Mitochondria, Liver; Calcium; Mitochondrial Swelling
PubMed: 38618716
DOI: 10.1161/CIRCRESAHA.123.323882 -
Cancer Medicine Aug 2023Hypoxic microenvironment is prominent in advanced esophageal squamous cell carcinoma (ESCC). However, it is unclear whether ESCC becomes hypoxic when it remains in the...
BACKGROUND
Hypoxic microenvironment is prominent in advanced esophageal squamous cell carcinoma (ESCC). However, it is unclear whether ESCC becomes hypoxic when it remains in the mucosal layer or as it invades the submucosal layer. We aimed to investigate whether intramucosal (Tis-T1a) or submucosal invasive (T1b) ESCC becomes hypoxic using endoscopic submucosal dissection samples.
METHODS
We evaluated the expression of hypoxia markers including hypoxia inducible factor 1α (HIF-1α), carbonic anhydrase IX (CAIX), and glucose transporter 1 (GLUT1) by H-score and vessel density by microvessel count (MVC) and microvessel density (MVD) for CD31 and α-smooth muscle actin (α-SMA) with immunohistochemical staining (n = 109). Further, we quantified oxygen saturation (StO ) with oxygen saturation endoscopic imaging (OXEI) (n = 16) and compared them to non-neoplasia controls, Tis-T1a, and T1b.
RESULTS
In Tis-T1a, cccIX (13.0 vs. 0.290, p < 0.001) and GLUT1 (199 vs. 37.6, p < 0.001) were significantly increased. Similarly, median MVC (22.7/mm vs. 14.2/mm , p < 0.001) and MVD (0.991% vs. 0.478%, p < 0.001) were markedly augmented. Additionally, in T1b, the mean expression of HIF-1α (16.0 vs. 4.95, p < 0.001), CAIX (15.7 vs. 0.290, p < 0.001), and GLUT1 (177 vs. 37.6, p < 0.001) were significantly heightened, and median MVC (24.8/mm vs. 14.2/mm , p < 0.001) and MVD (1.51% vs. 0.478%, p < 0.001) were markedly higher. Furthermore, OXEI revealed that median StO was significantly lower in T1b than in non-neoplasia (54% vs. 61.5%, p = 0.00131) and tended to be lower in T1b than in Tis-T1a (54% vs. 62%, p = 0.0606).
CONCLUSION
These results suggest that ESCC becomes hypoxic even at an early stage, and is especially prominent in T1b.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Immunohistochemistry; Glucose Transporter Type 1; Oxygen Saturation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; Tumor Microenvironment
PubMed: 37329213
DOI: 10.1002/cam4.6217 -
Physiological Reports Sep 2023Oxygen transport from the lungs to peripheral tissue is dependent on the affinity of hemoglobin for oxygen. Recent experimental data have suggested that the maximum...
Oxygen transport from the lungs to peripheral tissue is dependent on the affinity of hemoglobin for oxygen. Recent experimental data have suggested that the maximum human capacity for oxygen uptake and utilization (V̇O max) at sea level and altitude (~3000 m) is sensitive to alterations in hemoglobin-oxygen affinity. However, the effect of such alterations on V̇O max at extreme altitudes remains largely unknown due to the rarity of mutations affecting hemoglobin-oxygen affinity. This work uses a mathematical model that couples pulmonary oxygen uptake with systemic oxygen utilization under conditions of high metabolic demand to investigate the effect of hemoglobin-oxygen affinity on V̇O max as a function of altitude. The model includes the effects of both diffusive and convective limitations on oxygen transport. Pulmonary oxygen uptake is calculated using a spatially-distributed model that accounts for the effects of hematocrit and hemoglobin-oxygen affinity. Systemic oxygen utilization is calculated assuming Michaelis-Menten kinetics. The pulmonary and systemic model components are solved iteratively to compute predicted arterial and venous oxygen levels. Values of V̇O max are predicted for several values of hemoglobin-oxygen affinity and hemoglobin concentration based on data from humans with hemoglobin mutations. The model predicts that increased hemoglobin-oxygen affinity leads to increased V̇O max at altitudes above ~4500 m.
Topics: Humans; Altitude; Oxygen; Oxygen Consumption; Arteries; Hemoglobins
PubMed: 37653565
DOI: 10.14814/phy2.15806 -
Frontiers in Immunology 2023Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis... (Review)
Review
Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis (i.e., ATPase) domains, and power directional transport of diverse substrate classes - ions, small molecule metabolites, xenobiotics, hydrophobic drugs, and even polypeptides - into or out of cells or subcellular organelles. Although immunological functions of ABC transporters are only beginning to be unraveled, emerging literature suggests these proteins have under-appreciated roles in the development and function of T lymphocytes, including many of the key effector, memory and regulatory subsets that arise during responses to infection, inflammation or cancers. One transporter in particular, MDR1 (Multidrug resistance-1; encoded by the locus in humans), has taken center stage as a novel player in immune regulation. Although MDR1 remains widely viewed as a simple drug efflux pump in tumor cells, recent evidence suggests that this transporter fills key endogenous roles in enforcing metabolic fitness of activated CD4 and CD8 T cells. Here, we summarize current understanding of the physiological functions of ABC transporters in immune regulation, with a focus on the anti-oxidant functions of MDR1 that may shape both the magnitude and repertoires of antigen-specific effector and memory T cell compartments. While much remains to be learned about the functions of ABC transporters in immunobiology, it is already clear that they represent fertile new ground, both for the definition of novel immunometabolic pathways, and for the discovery of new drug targets that could be leveraged to optimize immune responses to vaccines and cancer immunotherapies.
Topics: Animals; Humans; Membrane Transport Proteins; ATP-Binding Cassette Transporters; Drug Resistance; Neoplasms; Adenosine Triphosphate; Mammals
PubMed: 38022644
DOI: 10.3389/fimmu.2023.1286696 -
Annals of the New York Academy of... Apr 2024The Hadley circulation (HC) is a global-scale atmospheric feature with air descending in the subtropics and ascending in the tropics, which plays a fundamental role in... (Review)
Review
The Hadley circulation (HC) is a global-scale atmospheric feature with air descending in the subtropics and ascending in the tropics, which plays a fundamental role in Earth's climate because it transports energy polewards and moisture equatorwards. Theoretically, as a consequence of anthropogenic climate change, the HC is expected to expand polewards, while indications on the HC strength are equivocal, as weakening and strengthening are expected in response to different mechanisms. In fact, there is a general agreement among reanalyses and climate simulations that the HC has significantly widened in the last four decades and it will continue widening in the future, but there is no consensus on past and future changes of the HC strength. Substantial uncertainties are produced by the effects of natural variability, structural deficiencies in climate models and reanalyses, and the influence of other forcing factors, such as anthropogenic aerosols, black carbon, and stratospheric and tropospheric ozone. The global HC can be decomposed into three regional HCs, associated with ascending motion above Equatorial Africa, the Maritime Continent, and Equatorial America, which have evolved differently during the last decades. Climate projections suggest a generalized expansion in the Southern Hemisphere, but a complex regional expansion/contraction pattern in the Northern Hemisphere.
Topics: Humans; Ozone; Climate Change; Climate Models
PubMed: 38532631
DOI: 10.1111/nyas.15114 -
Cardiovascular Research Mar 2024Damage of the blood-brain barrier (BBB) is a hallmark of brain injury during the early stages of ischemic stroke. The subsequent endothelial hyperpermeability drives the...
AIMS
Damage of the blood-brain barrier (BBB) is a hallmark of brain injury during the early stages of ischemic stroke. The subsequent endothelial hyperpermeability drives the initial pathological changes and aggravates neuronal death. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable nonselective cation channel activated by oxidative stress. However, whether TRPM2 is involved in BBB degradation during ischemic stroke remains unknown. We aimed to investigate the role of TRPM2 in BBB degradation during ischemic stroke and the underlying molecular mechanisms.
METHODS AND RESULTS
Specific deletion of Trpm2 in endothelial cells using Cdh5 Cre produces a potent protective effect against brain injury in mice subjected to middle cerebral artery occlusion (MCAO), which is characterized by reduced infarction size, mitigated plasma extravasation, suppressed immune cell invasion, and inhibited oxidative stress. In vitro experiments using cultured cerebral endothelial cells (CECs) demonstrated that either Trpm2 deletion or inhibition of TRPM2 activation attenuates oxidative stress, Ca2+ overload, and endothelial hyperpermeability induced by oxygen-glucose deprivation (OGD) and CD36 ligand thrombospondin-1 (TSP1). In transfected HEK293T cells, OGD and TSP1 activate TRPM2 in a CD36-dependent manner. Noticeably, in cultured CECs, deleting Trpm2 or inhibiting TRPM2 activation also suppresses the activation of CD36 and cellular dysfunction induced by OGD or TSP1.
CONCLUSIONS
In conclusion, our data reveal a novel molecular mechanism in which TRPM2 and CD36 promote the activation of each other, which exacerbates endothelial dysfunction during ischemic stroke. Our study suggests that TRPM2 in endothelial cells is a promising target for developing more effective and safer therapies for ischemic stroke.
Topics: Humans; Mice; Animals; Blood-Brain Barrier; Ischemic Stroke; Endothelial Cells; TRPM Cation Channels; Calcium; HEK293 Cells; Oxygen; Brain Injuries; Stroke; Brain Ischemia
PubMed: 37595268
DOI: 10.1093/cvr/cvad126 -
Critical Reviews in Biochemistry and... Dec 2023Hemoglobin (Hb) has been identified in at least 14 molluscan taxa so far. Research spanning over 130 years on molluscan Hbs focuses on their genes, protein structures,... (Review)
Review
Hemoglobin (Hb) has been identified in at least 14 molluscan taxa so far. Research spanning over 130 years on molluscan Hbs focuses on their genes, protein structures, functions, and evolution. Molluscan Hbs are categorized into single-, two-, and multiple-domain chains, including red blood cell, gill, and extracellular Hbs, based on the number of globin domains and their respective locations. These Hbs exhibit variation in assembly, ranging from monomeric and dimeric to higher-order multimeric forms. Typically, molluscan Hbs display moderately high oxygen affinity, weak cooperativity, and varying pH sensitivity. Hb's potential role in antimicrobial pathways could augment the immune defense of bivalves, which may be a complement to their lack of adaptive immunity. The role of Hb as a respiratory protein in bivalves likely originated from the substitution of hemocyanin. Molluscan Hbs demonstrate adaptive evolution in response to environmental changes via various strategies (e.g. increasing Hb types, multimerization, and amino acid residue substitutions at key sites), enhancing or altering functional properties for habitat adaptation. Concurrently, an increase in Hb assembly diversity, coupled with a downward trend in oxygen affinity, is observed during molluscan differentiation and evolution. Hb in Protobranchia, Heteroconchia, and Pteriomorphia bivalves originated from separate ancestors, with Protobranchia inheriting a relative ancient molluscan Hb gene. In bivalves, extracellular Hbs share a common origin, while gill Hbs likely emerged from convergent evolution. In summary, research on molluscan Hbs offers valuable insights into the origins, biological variations, and adaptive evolution of animal Hbs.
Topics: Animals; Hemoglobins; Mollusca; Oxygen
PubMed: 38189101
DOI: 10.1080/10409238.2023.2299381 -
British Journal of Anaesthesia Nov 2023Volatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur in rare cases, such as in certain genetic...
BACKGROUND
Volatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur in rare cases, such as in certain genetic disorders. Anaesthesia hypersensitivity is well-documented in a subset of mitochondrial diseases, but whether volatile anaesthetics are toxic in this setting has not been explored.
METHODS
We exposed Ndufs4(-/-) mice, a model of Leigh syndrome, to isoflurane (0.2-0.6%), oxygen 100%, or air. Cardiorespiratory function, weight, blood metabolites, and survival were assessed. We exposed post-symptom onset and pre-symptom onset animals and animals treated with the macrophage depleting drug PLX3397/pexidartinib to define the role of overt neuroinflammation in volatile anaesthetic toxicities.
RESULTS
Isoflurane induced hyperlactataemia, weight loss, and mortality in a concentration- and duration-dependent manner from 0.2% to 0.6% compared with carrier gas (O 100%) or mock (air) exposures (lifespan after 30-min exposures ∗P<0.05 for isoflurane 0.4% vs air or vs O, ∗∗P<0.005 for isoflurane 0.6% vs air or O; 60-min exposures ∗∗P<0.005 for isoflurane 0.2% vs air, ∗P<0.05 for isoflurane 0.2% vs O). Isoflurane toxicity was significantly reduced in Ndufs4(-/-) exposed before CNS disease onset, and the macrophage depleting drug pexidartinib attenuated sequelae of isoflurane toxicity (survival ∗∗∗P=0.0008 isoflurane 0.4% vs pexidartinib plus isoflurane 0.4%). Finally, the laboratory animal standard of care of 100% O as a carrier gas contributed significantly to weight loss and reduced survival, but not to metabolic changes, and increased acute mortality.
CONCLUSIONS
Isoflurane is toxic in the Ndufs4(-/-) model of Leigh syndrome. Toxic effects are dependent on the status of underlying neurologic disease, largely prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen concentration in the carrier gas.
Topics: Humans; Animals; Mice; Isoflurane; Anesthetics, Inhalation; Leigh Disease; Oxygen; Weight Loss; Electron Transport Complex I
PubMed: 37770252
DOI: 10.1016/j.bja.2023.08.009 -
Cerebral Cortex (New York, N.Y. : 1991) Jan 2024Normal cortical growth and the resulting folding patterns are crucial for normal brain function. Although cortical development is largely influenced by genetic factors,...
Normal cortical growth and the resulting folding patterns are crucial for normal brain function. Although cortical development is largely influenced by genetic factors, environmental factors in fetal life can modify the gene expression associated with brain development. As the placenta plays a vital role in shaping the fetal environment, affecting fetal growth through the exchange of oxygen and nutrients, placental oxygen transport might be one of the environmental factors that also affect early human cortical growth. In this study, we aimed to assess the placental oxygen transport during maternal hyperoxia and its impact on fetal brain development using MRI in identical twins to control for genetic and maternal factors. We enrolled 9 pregnant subjects with monochorionic diamniotic twins (30.03 ± 2.39 gestational weeks [mean ± SD]). We observed that the fetuses with slower placental oxygen delivery had reduced volumetric and surface growth of the cerebral cortex. Moreover, when the difference between placenta oxygen delivery increased between the twin pairs, sulcal folding patterns were more divergent. Thus, there is a significant relationship between placental oxygen transport and fetal brain cortical growth and folding in monochorionic twins.
Topics: Female; Humans; Pregnancy; Fetal Development; Fetal Growth Retardation; Oxygen; Placenta; Twins, Monozygotic
PubMed: 37885155
DOI: 10.1093/cercor/bhad383 -
Angewandte Chemie (International Ed. in... Feb 2024Cable bacteria are multicellular, filamentous bacteria that use internal conductive fibers to transfer electrons over centimeter distances from donors within anoxic...
Cable bacteria are multicellular, filamentous bacteria that use internal conductive fibers to transfer electrons over centimeter distances from donors within anoxic sediment layers to oxygen at the surface. We extracted the fibers and used them as free-standing bio-based electrodes to investigate their electrocatalytic behavior. The fibers catalyzed the reversible interconversion of oxygen and water, and an electric current was running through the fibers even when the potential difference was generated solely by a gradient of oxygen concentration. Oxygen reduction as well as oxygen evolution were confirmed by optical measurements. Within living cable bacteria, oxygen reduction by direct electrocatalysis on the fibers and not by membrane-bound proteins readily explains exceptionally high cell-specific oxygen consumption rates observed in the oxic zone, while electrocatalytic water oxidation may provide oxygen to cells in the anoxic zone.
Topics: Electron Transport; Geologic Sediments; Sulfides; Oxidation-Reduction; Bacteria; Oxygen; Water; Electrodes
PubMed: 38018379
DOI: 10.1002/anie.202312647