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    Hyperoxia Provokes Time- and Dose-Dependent Gut Injury and Endotoxemia and Alters Gut Microbiome and Transcriptome in Mice. Li Yunhang,Tao Yuanfa,Xu Jingyu,He Yihuai,Zhang Wen,Jiang Zhigang,He Ying,Liu Houmei,Chen Miao,Zhang Wei,Xing Zhouxiong Frontiers in medicine Oxygen therapy usually exposes patients to hyperoxia, which induces injuries in the lung, the heart, and the brain. The gut and its microbiome play key roles in critical illnesses, but the impact of hyperoxia on the gut and its microbiome remains not very clear. We clarified the time- and dose-dependent effects of hyperoxia on the gut and investigated oxygen-induced gut dysbiosis and explored the underlying mechanism of gut injury by transcriptome analysis. The C57BL/6 mice were randomly divided into the control group and nine different oxygen groups exposed to hyperoxia with an inspired O fraction (FiO) of 40, 60, and 80% for 24, 72, and 168 h (7 days), respectively. Intestinal histopathological and biochemical analyses were performed to explore the oxygen-induced gut injury and inflammatory response. Another experiment was performed to explore the impact of hyperoxia on the gut microbiome by exposing the mice to hyperoxia (FiO 80%) for 7 days, with the 16S rRNA sequencing method. We prolonged the exposure (up to 14 days) of the mice to hyperoxia (FiO 80%), and gut transcriptome analysis and western blotting were carried out to obtain differentially expressed genes (DEGs) and signaling pathways related to innate immunity and cell death. Inhaled oxygen induced time- and dose-dependent gut histopathological impairment characterized by mucosal atrophy (e.g., villus shortening: 80% of FiO for 24 h: = 0.008) and enterocyte death (e.g., apoptosis: 40% of FiO for 7 days: = 0.01). Administered time- and dose-dependent oxygen led to intestinal barrier dysfunction (e.g., endotoxemia: 80% of FiO for 72 h: = 0.002) and potentiated gut inflammation by increasing proinflammatory cytokines [e.g., tumor necrosis factor alpha (TNF-α): 40% of FiO for 24 h: = 0.003)] and reducing anti-inflammatory cytokines [Interleukin 10 (IL-10): 80% of FiO for 72 h: < 0.0001]. Hyperoxia induced gut dysbiosis with an expansion of oxygen-tolerant bacteria (e.g., ). Gut transcriptome analysis identified 1,747 DEGs and 171 signaling pathways and immunoblotting verified TLR-4, NOD-like receptor, and apoptosis signaling pathways were activated in oxygen-induced gut injury. Acute hyperoxia rapidly provokes gut injury in a time- and dose-dependent manner and induces gut dysbiosis, and an innate immune response is involved in an oxygen-induced gut injury. 10.3389/fmed.2021.732039
    Highs and lows of hyperoxia: physiological, performance, and clinical aspects. Brugniaux Julien Vincent,Coombs Geoff B,Barak Otto F,Dujic Zeljko,Sekhon Mypinder S,Ainslie Philip N American journal of physiology. Regulatory, integrative and comparative physiology Molecular oxygen (O) is a vital element in human survival and plays a major role in a diverse range of biological and physiological processes. Although normobaric hyperoxia can increase arterial oxygen content ([Formula: see text]), it also causes vasoconstriction and hence reduces O delivery in various vascular beds, including the heart, skeletal muscle, and brain. Thus, a seemingly paradoxical situation exists in which the administration of oxygen may place tissues at increased risk of hypoxic stress. Nevertheless, with various degrees of effectiveness, and not without consequences, supplemental oxygen is used clinically in an attempt to correct tissue hypoxia (e.g., brain ischemia, traumatic brain injury, carbon monoxide poisoning, etc.) and chronic hypoxemia (e.g., severe COPD, etc.) and to help with wound healing, necrosis, or reperfusion injuries (e.g., compromised grafts). Hyperoxia has also been used liberally by athletes in a belief that it offers performance-enhancing benefits; such benefits also extend to hypoxemic patients both at rest and during rehabilitation. This review aims to provide a comprehensive overview of the effects of hyperoxia in humans from the "bench to bedside." The first section will focus on the basic physiological principles of partial pressure of arterial O, [Formula: see text], and barometric pressure and how these changes lead to variation in regional O delivery. This review provides an overview of the evidence for and against the use of hyperoxia as an aid to enhance physical performance. The final section addresses pathophysiological concepts, clinical studies, and implications for therapy. The potential of O toxicity and future research directions are also considered. 10.1152/ajpregu.00165.2017
    The Impact of Short-Term Hyperoxia on Cerebral Metabolism: A Systematic Review and Meta-Analysis. Neurocritical care BACKGROUND:Cerebral ischemia due to hypoxia is a major cause of secondary brain injury and is associated with higher morbidity and mortality in patients with acute brain injury. Hyperoxia could improve energetic dysfunction in the brain in this setting. Our objectives were to perform a systematic review and meta-analysis of the current literature and to assess the impact of normobaric hyperoxia on brain metabolism by using cerebral microdialysis. METHODS:We searched Medline and Scopus, following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement; we searched for retrospective and prospective observational studies, interventional studies, and randomized clinical trials that performed a hyperoxia challenge in patients with acute brain injury who were concomitantly monitored with cerebral microdialysis. This study was registered in PROSPERO (CRD420211295223). RESULTS:We included a total of 17 studies, with a total of 311 patients. A statistically significant reduction in cerebral lactate values (pooled standardized mean difference [SMD] - 0.38 [- 0.53 to - 0.23]) and lactate to pyruvate ratio values (pooled SMD - 0.20 [- 0.35 to - 0.05]) was observed after hyperoxia. However, glucose levels (pooled SMD - 0.08 [- 0.23 to 0.08]) remained unchanged after hyperoxia. CONCLUSIONS:Normobaric hyperoxia may improve cerebral metabolic disturbances in patients with acute brain injury. The clinical impact of such effects needs to be further elucidated. 10.1007/s12028-022-01529-9
    Brief exposure to hyperoxia depletes the glial progenitor pool and impairs functional recovery after hypoxic-ischemic brain injury. Koch Joshua D,Miles Darryl K,Gilley Jennifer A,Yang Cui-Ping,Kernie Steven G Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Patterns of hypoxic-ischemic brain injury in infants and children suggest vulnerability in regions of white matter development, and injured patients develop defects in myelination resulting in cerebral palsy and motor deficits. Reperfusion exacerbates the oxidative stress that occurs after such injuries and may impair recovery. Resuscitation after hypoxic-ischemic injury is routinely performed using 100% oxygen, and this practice may increase the oxidative stress that occurs during reperfusion and further damage an already compromised brain. We show that brief exposure (30 mins) to 100% oxygen during reperfusion worsens the histologic injury in young mice after unilateral brain hypoxia-ischemia, causes an accumulation of the oxidative metabolite nitrotyrosine, and depletes preoligodendrocyte glial progenitors present in the cortex. This damage can be reversed with administration of the antioxidant ebselen, a glutathione peroxidase mimetic. Moreover, mice recovered in 100% oxygen have a more disrupted pattern of myelination and develop a static motor deficit that mimics cerebral palsy and manifests itself by significantly worse performance on wire hang and rotorod motor testing. We conclude that exposure to 100% oxygen during reperfusion after hypoxic-ischemic brain injury increases secondary neural injury, depletes developing glial progenitors, interferes with myelination, and ultimately impairs functional recovery. 10.1038/jcbfm.2008.15
    Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia. Serdar Meray,Herz Josephine,Kempe Karina,Lumpe Katharina,Reinboth Barbara S,Sizonenko Stéphane V,Hou Xinlin,Herrmann Ralf,Hadamitzky Martin,Heumann Rolf,Hansen Wiebke,Sifringer Marco,van de Looij Yohan,Felderhoff-Müser Ursula,Bendix Ivo Brain, behavior, and immunity Cerebral white matter injury is a leading cause of adverse neurodevelopmental outcome in prematurely born infants involving cognitive deficits in later life. Despite increasing knowledge about the pathophysiology of perinatal brain injury, therapeutic options are limited. In the adult demyelinating disease multiple sclerosis the sphingosine-1-phosphate (S1P) receptor modulating substance fingolimod (FTY720) has beneficial effects. Herein, we evaluated the neuroprotective potential of FTY720 in a neonatal model of oxygen-toxicity, which is associated with hypomyelination and impaired neuro-cognitive outcome. A single dose of FTY720 (1mg/kg) at the onset of neonatal hyperoxia (24h 80% oxygen on postnatal day 6) resulted in improvement of neuro-cognitive development persisting into adulthood. This was associated with reduced microstructural white matter abnormalities 4 months after the insult. In search of the underlying mechanisms potential non-classical (i.e. lymphocyte-independent) pathways were analysed shortly after the insult, comprising modulation of oxidative stress and local inflammatory responses as well as myelination, oligodendrocyte degeneration and maturation. Treatment with FTY720 reduced hyperoxia-induced oxidative stress, microglia activation and associated pro-inflammatory cytokine expression. In vivo and in vitro analyses further revealed that oxygen-induced hypomyelination is restored to control levels, which was accompanied by reduced oligodendrocyte degeneration and enhanced maturation. Furthermore, hyperoxia-induced elevation of S1P receptor 1 (S1P1) protein expression on in vitro cultured oligodendrocyte precursor cells was reduced by activated FTY720 and protection from degeneration is abrogated after selective S1P1 blockade. Finally, FTY720s' classical mode of action (i.e. retention of immune cells within peripheral lymphoid organs) was analysed demonstrating that FTY720 diminished circulating lymphocyte counts independent from hyperoxia. Cerebral immune cell counts remained unchanged by hyperoxia and by FTY720 treatment. Taken together, these results suggest that beneficial effects of FTY720 in neonatal oxygen-induced brain injury may be rather attributed to its anti-oxidative and anti-inflammatory capacity acting in concert with a direct protection of developing oligodendrocytes than to a modulation of peripheral lymphocyte trafficking. Thus, FTY720 might be a potential new therapeutic option for the treatment of neonatal brain injury through reduction of white matter damage. 10.1016/j.bbi.2015.10.004
    Traumatic brain injury: physiological targets for clinical practice in the prehospital setting and on the Neuro-ICU. Wijayatilake Dhuleep S,Jigajinni Suyogi V,Sherren Peter B Current opinion in anaesthesiology PURPOSE OF REVIEW:Over many years, understanding of the pathophysiology in traumatic brain injury (TBI) has resulted in the development of core physiological targets and therapies to preserve cerebral oxygenation, and in doing so prevent secondary insult. The present review revisits the evidence for these targets and therapies. RECENT FINDINGS:Achieving oxygen, carbon dioxide, blood pressure, temperature and glucose targets remain a key goal of therapy in TBI, as does the role of effective prehospital care. Physician led air ambulance teams reduce mortality. Normobaric hyperoxia is dangerous to the injured brain; as are both high and low carbon dioxide levels. Hypotension is life threatening and higher targets have now been suggested in TBI. Both therapeutic normothermia and hypothermia have a role in specific groups of patients with TBI. Although consensus has not been reached on the optimal intravenous fluid for resuscitation in TBI, vigilant goal-directed fluid administration may improve outcome. Osmotherapeutic agents such as hypertonic sodium lactate solutions may also have a role alongside conventional agents. SUMMARY:Maintaining physiological targets in several areas remains part of protocol led care in the acute phase of TBI management. As evidence accumulates however, the target values and therefore therapies may be set to change. 10.1097/ACO.0000000000000233
    Comparative Response of Brain to Chronic Hypoxia and Hyperoxia. Terraneo Laura,Samaja Michele International journal of molecular sciences Two antithetic terms, hypoxia and hyperoxia, i.e., insufficient and excess oxygen availability with respect to needs, are thought to trigger opposite responses in cells and tissues. This review aims at summarizing the molecular and cellular mechanisms underlying hypoxia and hyperoxia in brain and cerebral tissue, a context that may prove to be useful for characterizing not only several clinically relevant aspects, but also aspects related to the evolution of oxygen transport and use by the tissues. While the response to acute hypoxia/hyperoxia presumably recruits only a minor portion of the potentially involved cell machinery, focusing into chronic conditions, instead, enables to take into consideration a wider range of potential responses to oxygen-linked stress, spanning from metabolic to genic. We will examine how various brain subsystems, including energetic metabolism, oxygen sensing, recruitment of pro-survival pathways as protein kinase B (Akt), mitogen-activated protein kinases (MAPK), neurotrophins (BDNF), erythropoietin (Epo) and its receptors (EpoR), neuroglobin (Ngb), nitric oxide (NO), carbon monoxide (CO), deal with chronic hypoxia and hyperoxia to end-up with the final outcomes, oxidative stress and brain damage. A more complex than expected pattern results, which emphasizes the delicate balance between the severity of the stress imposed by hypoxia and hyperoxia and the recruitment of molecular and cellular defense patterns. While for certain functions the expectation that hypoxia and hyperoxia should cause opposite responses is actually met, for others it is not, and both emerge as dangerous treatments. 10.3390/ijms18091914
    A neonatal mouse model of intermittent hypoxia associated with features of apnea in premature infants. Cai Jun,Tuong Chi Minh,Gozal David Respiratory physiology & neurobiology A neonatal mouse model of intermittent hypoxia (IH) simulating the recurring hypoxia/reoxygenation episodes of apnea of prematurity (AOP) was developed. C57BL/6 P2 pups were culled for exposure to either intermittent hypoxia or intermittent air as control. The IH paradigms consisted of alternation cycles of 20.9% O2 and either 8.0% or 5.7% O2 every 120 or 140s for 6h a day during daylight hours from day 2 to day 10 postnatally, i.e., roughly equivalent to human brain development in the perinatal period. IH exposures elicited modest to severe decrease in oxygen saturation along with bradycardia in neonatal mice, which were severity-dependent. Hypomyelination in both central and peripheral nervous systems was observed despite the absence of visible growth retardation. The neonatal mouse model of IH in this study partially fulfills the current diagnostic criteria with features of AOP, and provides opportunities to reproduce in rodents some of the pathophysiological changes associated with this disorder, such as alterations in myelination. 10.1016/j.resp.2011.06.003
    Perinatal Hyperoxia and Developmental Consequences on the Lung-Brain Axis. Obst Stefanie,Herz Josephine,Alejandre Alcazar Miguel A,Endesfelder Stefanie,Möbius Marius A,Rüdiger Mario,Felderhoff-Müser Ursula,Bendix Ivo Oxidative medicine and cellular longevity Approximately 11.1% of all newborns worldwide are born preterm. Improved neonatal intensive care significantly increased survival rates over the last decades but failed to reduce the risk for the development of chronic lung disease (i.e., bronchopulmonary dysplasia (BPD)) and impaired neurodevelopment (i.e., encephalopathy of prematurity (EoP)), two major long-term sequelae of prematurity. Premature infants are exposed to relative hyperoxia, when compared to physiological in-utero conditions and, if needed to additional therapeutic oxygen supplementation. Both are associated with an increased risk for impaired organ development. Since the detrimental effects of hyperoxia on the immature retina are known for many years, lung and brain have come into focus in the last decade. Hyperoxia-induced excessive production of reactive oxygen species leading to oxidative stress and inflammation contribute to pulmonary growth restriction and abnormal neurodevelopment, including myelination deficits. Despite a large body of studies, which unraveled important pathophysiological mechanisms for both organs at risk, the majority focused exclusively either on lung or on brain injury. However, considering that preterm infants suffering from BPD are at higher risk for poor neurodevelopmental outcome, an interaction between both organs seems plausible. This review summarizes recent findings regarding mechanisms of hyperoxia-induced neonatal lung and brain injury. We will discuss common pathophysiological pathways, which potentially link both injured organ systems. Furthermore, promises and needs of currently suggested therapies, including pharmacological and regenerative cell-based treatments for BPD and EoP, will be emphasized. Limited therapeutic approaches highlight the urgent need for a better understanding of the mechanisms underlying detrimental effects of hyperoxia on the lung-brain axis in order to pave the way for the development of novel multimodal therapies, ideally targeting both severe preterm birth-associated complications. 10.1155/2022/5784146
    Oxygen radical disease in the newborn, revisited: Oxidative stress and disease in the newborn period. Perez Marta,Robbins Mary E,Revhaug Cecilie,Saugstad Ola D Free radical biology & medicine Thirty years ago, there was an emerging appreciation for the significance of oxidative stress in newborn disease. This prompted a renewed interest in the impact of oxygen therapy for the newborn in the delivery room and beyond, especially in premature infants. Today, the complexity of oxidative stress both in normal regulation and pathology is better understood, especially as it relates to neonatal mitochondrial oxidative stress responses to hyperoxia. Mitochondria are recipients of oxidative damage and have a propensity for oxidative self-injury that has been implicated in the pathogenesis of neonatal lung diseases. Similarly, both intrauterine growth restriction (IUGR) and macrosomia are associated with mitochondrial dysfunction and oxidative stress. Additionally, reoxygenation with 100% O in a hypoxic-ischemic newborn lamb model increased the production of pro-inflammatory cytokines in the brain. Moreover, the interplay between inflammation and oxidative stress in the newborn is better understood because of animal studies. Transcriptomic analyses have found a number of genes to be differentially expressed in murine models of bronchopulmonary dysplasia (BPD). Epigenetic changes have also been detected both in animal models of BPD and premature infants exposed to oxygen. Antioxidant therapy to prevent newborn disease has not been very successful; however, new therapeutic principles, like melatonin, are under investigation. 10.1016/j.freeradbiomed.2019.03.035
    2-PMAP Ameliorates Cerebral Vasospasm and Brain Injury after Subarachnoid Hemorrhage by Regulating Neuro-Inflammation in Rats. Wu Chieh-Hsin,Tsai Hung-Pei,Su Yu-Feng,Tsai Cheng-Yu,Lu Ying-Yi,Lin Chih-Lung Cells A subarachnoid hemorrhage (SAH), leading to severe disability and high fatality in survivors, is a devastating disease. Neuro-inflammation, a critical mechanism of cerebral vasospasm and brain injury from SAH, is tightly related to prognoses. Interestingly, studies indicate that 2-[(pyridine-2-ylmethyl)-amino]-phenol (2-PMAP) crosses the blood-brain barrier easily. Here, we investigated whether the vasodilatory and neuroprotective roles of 2-PMAP were observed in SAH rats. Rats were assigned to three groups: sham, SAH and SAH+2-PMAP. SAHs were induced by a cisterna magna injection. In the SAH+2-PMAP group, 5 mg/kg 2-PMAP was injected into the subarachnoid space before SAH induction. The administration of 2-PMAP markedly ameliorated cerebral vasospasm and decreased endothelial apoptosis 48 h after SAH. Meanwhile, 2-PMAP decreased the severity of neurological impairments and neuronal apoptosis after SAH. Furthermore, 2-PMAP decreased the activation of microglia and astrocytes, expressions of TLR-4 and p-NF-κB, inflammatory markers (TNF-α, IL-1β and IL-6) and reactive oxygen species. This study is the first to confirm that 2-PMAP has vasodilatory and neuroprotective effects in a rat model of SAH. Taken together, the experimental results indicate that 2-PMAP treatment attenuates neuro-inflammation, oxidative stress and cerebral vasospasm, in addition to ameliorating neurological deficits, and that these attenuating and ameliorating effects are conferred through the TLR-4/NF-κB pathway. 10.3390/cells11020242
    Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases. Cruz-Haces Marcela,Tang Jonathan,Acosta Glen,Fernandez Joseph,Shi Riyi Translational neurodegeneration Traumatic brain injury is among the most common causes of death and disability in youth and young adults. In addition to the acute risk of morbidity with moderate to severe injuries, traumatic brain injury is associated with a number of chronic neurological and neuropsychiatric sequelae including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, despite the high incidence of traumatic brain injuries and the established clinical correlation with neurodegeneration, the causative factors linking these processes have not yet been fully elucidated. Apart from removal from activity, few, if any prophylactic treatments against post-traumatic brain injury neurodegeneration exist. Therefore, it is imperative to understand the pathophysiological mechanisms of traumatic brain injury and neurodegeneration in order to identify potential factors that initiate neurodegenerative processes. Oxidative stress, neuroinflammation, and glutamatergic excitotoxicity have previously been implicated in both secondary brain injury and neurodegeneration. In particular, reactive oxygen species appear to be key in mediating molecular insult in neuroinflammation and excitotoxicity. As such, it is likely that post injury oxidative stress is a key mechanism which links traumatic brain injury to increased risk of neurodegeneration. Consequently, reactive oxygen species and their subsequent byproducts may serve as novel fluid markers for identification and monitoring of cellular damage. Furthermore, these reactive species may further serve as a suitable therapeutic target to reduce the risk of post-injury neurodegeneration and provide long term quality of life improvements for those suffering from traumatic brain injury. 10.1186/s40035-017-0088-2
    Harmful Effects of Hyperoxia in Postcardiac Arrest, Sepsis, Traumatic Brain Injury, or Stroke: The Importance of Individualized Oxygen Therapy in Critically Ill Patients. Vincent Jean-Louis,Taccone Fabio Silvio,He Xinrong Canadian respiratory journal The beneficial effects of oxygen are widely known, but the potentially harmful effects of high oxygenation concentrations in blood and tissues have been less widely discussed. Providing supplementary oxygen can increase oxygen delivery in hypoxaemic patients, thus supporting cell function and metabolism and limiting organ dysfunction, but, in patients who are not hypoxaemic, supplemental oxygen will increase oxygen concentrations into nonphysiological hyperoxaemic ranges and may be associated with harmful effects. Here, we discuss the potentially harmful effects of hyperoxaemia in various groups of critically ill patients, including postcardiac arrest, traumatic brain injury or stroke, and sepsis. In all these groups, there is evidence that hyperoxia can be harmful and that oxygen prescription should be individualized according to repeated assessment of ongoing oxygen requirements. 10.1155/2017/2834956
    Hyperoxia and the Immature Brain. Reich Bettina,Hoeber Daniela,Bendix Ivo,Felderhoff-Mueser Ursula Developmental neuroscience Despite major advances in obstetrics and neonatal intensive care, preterm infants frequently suffer from neurological impairments in later life. Preterm and also full-term neonates are generally susceptible to injury caused by reactive oxygen species due to the immaturity of endogenous radical scavenging systems. It is well known that high oxygen levels experienced during the critical phase of maturation can profoundly influence developmental processes. Supraphysiological oxygen concentrations used for resuscitation or in the care of critically ill infants are known to have deleterious effects on the developing lung and retina, contributing to the pathophysiology of neonatal diseases like bronchopulmonary dysplasia and retinopathy of prematurity. Moreover, experimental work from the last decade suggests that hyperoxia also leads to neuronal and glial cell death, contributing to the injury of white and grey matter observed in preterm infants. During the critical phase of brain maturation, hyperoxia can alter developmental processes, resulting in the disruption of neural plasticity and myelination. However, oxygen therapy can often not be avoided in neonatal intensive care. Therefore, in situations requiring oxygen supplementation, in addition to the development of appropriate monitoring systems, protective and/or regenerative strategies are highly warranted. Here, we summarise the clinical and experimental evidence as well as potential therapeutic strategies, providing an overview of the pathophysiology of oxygen exposure on the developing central nervous system and its impact on neonatal brain injury. 10.1159/000454917
    Theaflavin alleviates inflammatory response and brain injury induced by cerebral hemorrhage via inhibiting the nuclear transcription factor kappa β-related pathway in rats. Drug design, development and therapy OBJECTIVE:Intracerebral hemorrhage (ICH) is one of the most common acute cerebrovascular diseases with high mortality. Numerous studies have shown that inflammatory response played an important role in ICH-induced brain injury. Theaflavin (TF) extracted from black tea has various biological functions including anti-inflammatory activity. In this study, we investigated whether TF could inhibit ICH-induced inflammatory response in rats and explored its mechanism. MATERIALS AND METHODS:ICH rat models were induced with type VII collagenase and pretreated with TF by gavage in different doses (25 mg/kg-100 mg/kg). Twenty-four hours after ICH attack, we evaluated the rats' behavioral performance, the blood-brain barrier (BBB) integrity, and the formation of cerebral edema. The levels of reactive oxygen species (ROS) and inflammatory cytokines were examined by 2',7'-dichlorofluorescin diacetate and enzyme-linked immunosorbent assay. Nissl staining and transferase dUTP nick end labeling (TUNEL) were aimed to detect the neuron loss and apoptosis, the mechanism of which was explored by Western blot. RESULTS:It was found that in the pretreated ICH rats TF significantly alleviated the behavioral defects, protected BBB integrity, and decreased the formation of cerebral edema and the levels of ROS as well as inflammatory cytokines (including interleukin-1 beta [IL-1β], IL-18, tumor nectosis factor-alpha, interferon-γ, transforming growth factor beta, and (C-X-C motif) ligand 1 [CXCL1]). Nissl staining and TUNEL displayed TF could protect against the neuron loss and apoptosis via inhibiting the activation of nuclear transcription factor kappa-β-p65 (NF-κβ-p65), caspase-1, and IL-1β. We also found that phorbol 12-myristate 13-acetate, a nonspecific activator of NF-κβ-p65, weakened the positive effect of TF on ICH-induced neural defects and neuron apoptosis by upregulating NF-κβ-related signaling pathway. CONCLUSION:TF could alleviate ICH-induced inflammatory responses and brain injury in rats via inhibiting NF-κβ-related pathway, which may provide a new way for the therapy of ICH. 10.2147/DDDT.S164324
    Protective effect of telmisartan against progressive oxidative brain damage and synuclein phosphorylation in stroke-resistant spontaneously hypertensive rats. Fukui Yusuke,Yamashita Toru,Kurata Tomoko,Sato Kota,Lukic Violeta,Hishikawa Nozomi,Deguchi Kentaro,Abe Koji Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Previously, we reported that reactive oxygen species and signaling molecules of angiotensin II produced lipid peroxides, degenerated proteins, and injured DNA after cerebral ischemia in normotensive Wistar rats. Here, we investigated the long-term effect of the angiotensin II type I receptor blocker telmisartan on oxidative stress and hyperphosphorylated α-synuclein accumulation in stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 3 months, SHR-SR were divided into 3 treatment groups: SHR-SR vehicle (SHR/Ve), SHR-SR low-dose telmisartan (.3 mg/kg/day) (SHR/low), and SHR-SR high-dose telmisartan (3 mg/kg/day) (SHR/high). Immunohistologic analyses were conducted in these groups and Wistar rats at the age of 6, 12, and 18 months. The SHR/Ve group demonstrated more progressive increase in advanced glycation end product (AGE)-, 4-hydroxy-2-nonenal (4-HNE)-, and phosphorylated α-synuclein (pSyn)-positive cells in the cerebral cortex and hippocampus compared with the Wistar group at 18 months. These expressions were reduced in the SHR/low group even without lowering blood pressure (BP), and expressions were dramatically suppressed in the SHR/high group with lowering of BP. These data suggest that persistent hypertension in SHR-SR strongly potentiate the markers of oxidative damage (AGEs and 4-HNE) and abnormal accumulation of pSyn, which were greatly suppressed by telmisartan in a dose-dependent manner without and with lowering of BP. 10.1016/j.jstrokecerebrovasdis.2013.12.052
    The common antitussive agent dextromethorphan protects against hyperoxia-induced cell death in established in vivo and in vitro models of neonatal brain injury. Posod A,Pinzer K,Urbanek M,Wegleiter K,Keller M,Kiechl-Kohlendorfer U,Griesmaier E Neuroscience Preterm infants are prematurely subjected to relatively high oxygen concentrations, even when supplemental oxygen is not administered. There is increasing evidence to show that an excess of oxygen is toxic to the developing brain. Dextromethorphan (DM), a frequently used antitussive agent with pleiotropic mechanisms of action, has been shown to be neuroprotective in various models of central nervous system pathology. Due to its numerous beneficial properties, it might also be able to counteract detrimental effects of a neonatal oxygen insult. The aim of the current study was to evaluate its therapeutic potential in established cell culture and rodent models of hyperoxia-induced neonatal brain injury. For in vitro studies pre- and immature oligodendroglial (OLN-93) cells were subjected to hyperoxic conditions for 48 h after pre-treatment with increasing doses of DM. For in vivo studies 6-day-old Wistar rat pups received a single intraperitoneal injection of DM in two different dosages prior to being exposed to hyperoxia for 24h. Cell viability and caspase-3 activation were assessed as outcome parameters at the end of exposure. DM significantly increased cell viability in immature oligodendroglial cells subjected to hyperoxia. In pre-oligodendroglial cells cell viability was not significantly affected by DM treatment. In vivo caspase-3 activation induced by hyperoxic exposure was significantly lower after administration of DM in gray and white matter areas. In control animals kept under normoxic conditions DM did not significantly influence caspase-3-dependent apoptosis. The present results indicate that DM is a promising and safe treatment strategy for neonatal hyperoxia-induced brain injury that merits further investigation. 10.1016/j.neuroscience.2014.05.059
    A Fluorogenic ONOO-Triggered Carbon Monoxide Donor for Mitigating Brain Ischemic Damage. Xing Linfeng,Wang Bin,Li Jin,Guo Xinjian,Lu Xicun,Chen Xiaohua,Sun Haitao,Sun Zhenrong,Luo Xiao,Qi Suhua,Qian Xuhong,Yang Youjun Journal of the American Chemical Society Ischemia-reperfusion (I/R) injuries are from the secondary radicals of ONOO. Direct radical scavenging is difficult because of their high reactivity. ONOO is longer-lived than the radicals in the biological milieu. Scavenging ONOO suppresses radical generation preventively. CO is neuroprotective during ischemia. With the scaffold of carbon-caged xanthene, we designed an OONO-triggered CO donor (). Notably, exhibited a concomitant fluorescence turn-on upon ONOOdetection, facilitating microscopic monitoring. was cytoprotective in oxygen-glucose deprivation (OGD)-insulted PC-12 cells. It was permeable to the blood-brain barrier and further exhibited neuroprotective effects to MCAO rats by reducing infarction volume, cell apoptosis, and brain edema. 10.1021/jacs.2c00094
    Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states. Hahl Peter,Davis Taron,Washburn Cecilia,Rogers Jack T,Smith Ann Journal of neurochemistry Hemopexin provides neuroprotection in mouse models of stroke and intracerebral hemorrhage and protects neurons in vitro against heme or reactive oxygen species (ROS) toxicity via heme oxygenase-1 (HO1) activity. To model human brain neurons experiencing hemorrhages and inflammation, we used human neuroblastoma cells, heme-hemopexin complexes, and physiologically relevant ROS, for example, H(2)O(2) and HOCl, to provide novel insights into the underlying mechanism whereby hemopexin safely maintains heme and iron homeostasis. Human amyloid precursor protein (hAPP), needed for iron export from neurons, is induced ~twofold after heme-hemopexin endocytosis by iron from heme catabolism via the iron-regulatory element of hAPP mRNA. Heme-hemopexin is relatively resistant to damage by ROS and retains its ability to induce the cytoprotective HO1 after exposure to tert-butylhydroperoxide, although induction is impaired, but not eliminated, by exposure to high concentrations of H(2)O(2) in vitro. Apo-hemopexin, which predominates in non-hemolytic states, resists damage by H(2)O(2) and HOCl, except for the highest concentrations likely in vivo. Heme-albumin and albumin are preferential targets for ROS; thus, albumin protects hemopexin in biological fluids like CSF and plasma where it is abundant. These observations provide strong evidence that hemopexin will be neuroprotective after traumatic brain injury, with heme release in the CNS, and during the ensuing inflammation. Hemopexin sequesters heme, thus preventing unregulated heme uptake that leads to toxicity; it safely delivers heme to neuronal cells; and it activates the induction of proteins including HO1 and hAPP that keep heme and iron at safe levels in neurons. 10.1111/jnc.12165
    Resveratrol Treatment Prevents Hippocampal Neurodegeneration in a Rodent Model of Traumatic Brain Injury. Atalay Tugay,Gulsen Ismail,Colcimen Nese,Alp Hamit Hakan,Sosuncu Enver,Alaca Ilker,Ak Hakan,Ragbetli Murat Cetin Turkish neurosurgery AIM:Traumatic brain injury (TBI) is a complex process. Increasing evidence has demonstrated that reactive oxygen species contribute to brain injury. Resveratrol (RVT) which exhibits significant antioxidant properties, is neuroprotective against excitotoxicity, ischemia, and hypoxia. The aim of this study was to evaluate the neuroprotective effects of RVT on the hippocampus of a rat model of TBI. MATERIAL AND METHODS:Twenty eight rats were divided into four groups. A moderate degree of head trauma was induced using Feeney"s falling weight technique. Group 1 (control) underwent no intervention or treatment. Head trauma was induced in Group 2 (trauma) and no drug was administered. Head trauma was induced in Group 3 and low-dose RVT (50 mg/kg per day) was injected. In Group 4, high-dose RVT (100 mg/kg per day) was used after head trauma. Brain tissues were extracted immediately after perfusion without damaging the tissues. Histopathological and biochemistry parameters were studied. RESULTS:Brain tissue malondialdehyde (MDA) levels in the trauma group were significantly higher than those in the control, lowdose RVT-treated, and high-dose-RVT-treated groups. The superoxide dismutase (SOD) levels in the control group were significantly higher than those in the trauma, low-dose RVT-treated, and high-dose RVT-treated groups. Glutathione peroxidase (GSH-Px) levels in the control group were significantly higher than those in the trauma and low-dose RVT-treated groups. The level of oxidative deoxyribonucleic acid (DNA) damage (8-OHdG/106 dG) in the trauma group was higher than that in the control group, low-dose RVT-treated, and high-dose RVT-treated groups. CONCLUSION:Resveratrol has a healing effect on neurons after TBI. 10.5137/1019-5149.JTN.17249-16.2
    GDF11 alleviates secondary brain injury after intracerebral hemorrhage via attenuating mitochondrial dynamic abnormality and dysfunction. Xiao Anqi,Zhang Yiqi,Ren Yanming,Chen Ruiqi,Li Tao,You Chao,Gan Xueqi Scientific reports Intracerebral hemorrhage (ICH) is a serious public health problem with high rates of death and disability. The neuroprotective effect of Growth Differentiation Factor 11 (GDF11) in ICH has been initially proved by our previous study. Oxidative stress (OS) plays crucial roles in mediating subsequent damage of ICH. However, whether and how mitochondrial dynamic events and function participated in ICH pathophysiology, and how mitochondrial function and OS interreacted in the neuroprotective process of GDF11 in ICH remains unclarified. Based on the rat model of ICH and in vitro cell model, we demonstrated that GDF11 could alleviate ICH induced neurological deficits, brain edema, OS status, neuronal apoptosis and inflammatory reaction. In addition, mitochondrial functional and structural impairments were obviously restored by GDF11. Treatment with antioxidant protected against erythrocyte homogenate (EH) induced cell injury by restoring OS status and mitochondrial fusion fission imbalance, which was similar to the effect of GDF11 treatment. Further, inhibition of mitochondrial division with Mdivi-1 attenuated mitochondrial functional defects and neuronal damages. In conclusion, our results for the first time proposed that GDF11 protected the post-ICH secondary injury by suppressing the feedback loop between mitochondrial ROS production and mitochondrial dynamic alteration, resulting in attenuated mitochondrial function and amelioration of neural damage. 10.1038/s41598-021-83545-x
    Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III). Pérez-De La Cruz V,González-Cortés C,Galván-Arzate S,Medina-Campos O N,Pérez-Severiano F,Ali S F,Pedraza-Chaverrí J,Santamaría A Neuroscience Oxidative/nitrosative stress is involved in NMDA receptor-mediated excitotoxic brain damage produced by the glutamate analog quinolinic acid. The purpose of this work was to study a possible role of peroxynitrite, a reactive oxygen/nitrogen species, in the course of excitotoxic events evoked by quinolinic acid in the brain. The effects of Fe(TPPS) (5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III)), an iron porphyrinate and putative peroxynitrite decomposition catalyst, were tested on lipid peroxidation and mitochondrial function in brain synaptic vesicles exposed to quinolinic acid, as well as on peroxynitrite formation, nitric oxide synthase and superoxide dismutase activities, lipid peroxidation, caspase-3-like activation, DNA fragmentation, and GABA levels in striatal tissue from rats lesioned by quinolinic acid. Circling behavior was also evaluated. Increasing concentrations of Fe(TPPS) reduced lipid peroxidation and mitochondrial dysfunction induced by quinolinic acid (100 microM) in synaptic vesicles in a concentration-dependent manner (10-800 microM). In addition, Fe(TPPS) (10 mg/kg, i.p.) administered 2 h before the striatal lesions, prevented the formation of peroxynitrite, the increased nitric oxide synthase activity, the decreased superoxide dismutase activity and the increased lipid peroxidation induced by quinolinic acid (240 nmol/microl) 120 min after the toxin infusion. Enhanced caspase-3-like activity and DNA fragmentation were also reduced by the porphyrinate 24 h after the injection of the excitotoxin. Circling behavior from quinolinic acid-treated rats was abolished by Fe(TPPS) six days after quinolinic acid injection, while the striatal levels of GABA, measured one day later, were partially recovered. The protective effects that Fe(TPPS) exerted on quinolinic acid-induced lipid peroxidation and mitochondrial dysfunction in synaptic vesicles suggest a primary action of the porphyrinate as an antioxidant molecule. In vivo findings suggest that the early production of peroxynitrite, altogether with the enhanced risk of superoxide anion (O2*-) and nitric oxide formation (its precursors) induced by quinolinic acid in the striatum, are attenuated by Fe(TPPS) through a recovery in the basal activities of nitric oxide synthase and superoxide dismutase. The porphyrinate-mediated reduction in DNA fragmentation simultaneous to the decrease in caspase-3-like activation from quinolinic acid-lesioned rats suggests a prevention in the risk of peroxynitrite-mediated apoptotic events during the course of excitotoxic damage in the striatum. In summary, the protective effects that Fe(TPPS) exhibited both under in vitro and in vivo conditions support an active role of peroxynitrite and its precursors in the pattern of brain damage elicited by excitotoxic events in the experimental model of Huntington's disease. The neuroprotective mechanisms of Fe(TPPS) are discussed. 10.1016/j.neuroscience.2005.06.027
    Traumatic brain injury: oxidative stress and neuroprotection. Cornelius Carolin,Crupi Rosalia,Calabrese Vittorio,Graziano Antonio,Milone Pietro,Pennisi Giovanni,Radak Zsolt,Calabrese Edward J,Cuzzocrea Salvatore Antioxidants & redox signaling SIGNIFICANCE:A vast amount of circumstantial evidence implicates high energy oxidants and oxidative stress as mediators of secondary damage associated with traumatic brain injury. The excessive production of reactive oxygen species due to excitotoxicity and exhaustion of the endogenous antioxidant system induces peroxidation of cellular and vascular structures, protein oxidation, cleavage of DNA, and inhibition of the mitochondrial electron transport chain. RECENT ADVANCES:Different integrated responses exist in the brain to detect oxidative stress, which is controlled by several genes termed vitagens. Vitagens encode for cytoprotective heat shock proteins, and thioredoxin and sirtuins. CRITICAL ISSUES AND FUTURE DIRECTIONS:This article discusses selected aspects of secondary brain injury after trauma and outlines key mechanisms associated with toxicity, oxidative stress, inflammation, and necrosis. Finally, this review discusses the role of different oxidants and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with brain trauma. 10.1089/ars.2012.4981
    Arctic ground squirrel resist peroxynitrite-mediated cell death in response to oxygen glucose deprivation. Bhowmick Saurav,Drew Kelly L Free radical biology & medicine Cerebral ischemia-reperfusion (I/R) injury initiates a cascade of events, generating nitric oxide (NO) and superoxide(O) to form peroxynitrite (ONOO), a potent oxidant. Arctic ground squirrels (AGS; Urocitellus parryii) show high tolerance to I/R injury. However, the underlying mechanism remains elusive. We hypothesize that tolerance to I/R modeled in an acute hippocampal slice preparation in AGS is modulated by reduced oxidative and nitrative stress. Hippocampal slices (400µm) from rat and AGS were subjected to oxygen glucose deprivation (OGD) using a novel microperfusion technique. Slices were exposed to NO, O donors with and without OGD; pretreatment with inhibitors of NO, O and ONOO followed by OGD. Perfusates collected every 15min were analyzed for LDH release, a marker of cell death. 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE) were measured to assess oxidative and nitrative stress. Results show that NO/O alone is not sufficient to cause ischemic-like cell death, but with OGD enhances cell death more in rat than in AGS. A NOS inhibitor, SOD mimetic and ONOO inhibitor attenuates OGD injury in rat but has no effect in AGS. Rats also show a higher level of 3NT and 4HNE with OGD than AGS suggesting the greater level of injury in rat is via formation of ONOO. 10.1016/j.freeradbiomed.2017.09.024
    Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury. Wang Han,Zhou Xiao-Ming,Wu Ling-Yun,Liu Guang-Jie,Xu Wei-Dong,Zhang Xiang-Sheng,Gao Yong-Yue,Tao Tao,Zhou Yan,Lu Yue,Wang Juan,Deng Chu-Lei,Zhuang Zong,Hang Chun-Hua,Li Wei Journal of neuroinflammation BACKGROUND:Aucubin (Au), an iridoid glycoside from natural plants, has antioxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in an HO-induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model. METHODS:In vitro experiments, the various concentrations of Au (50 μg/ml, 100 μg/ml, or 200 μg/ml) were added in culture medium at 0 h and 6 h after neurons stimulated by HO (100 μM). After exposed for 12 h, neurons were collected for western blot (WB), immunofluorescence, and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits, and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry, and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR. RESULTS:Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS), and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages, and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1 (HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au. CONCLUSIONS:Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system. 10.1186/s12974-020-01863-9
    Low-level light in combination with metabolic modulators for effective therapy of injured brain. Dong Tingting,Zhang Qi,Hamblin Michael R,Wu Mei X Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Vascular damage occurs frequently at the injured brain causing hypoxia and is associated with poor outcomes in the clinics. We found high levels of glycolysis, reduced adenosine triphosphate generation, and increased formation of reactive oxygen species and apoptosis in neurons under hypoxia. Strikingly, these adverse events were reversed significantly by noninvasive exposure of injured brain to low-level light (LLL). Low-level light illumination sustained the mitochondrial membrane potential, constrained cytochrome c leakage in hypoxic cells, and protected them from apoptosis, underscoring a unique property of LLL. The effect of LLL was further bolstered by combination with metabolic substrates such as pyruvate or lactate both in vivo and in vitro. The combinational treatment retained memory and learning activities of injured mice to a normal level, whereas other treatment displayed partial or severe deficiency in these cognitive functions. In accordance with well-protected learning and memory function, the hippocampal region primarily responsible for learning and memory was completely protected by combination treatment, in marked contrast to the severe loss of hippocampal tissue because of secondary damage in control mice. These data clearly suggest that energy metabolic modulators can additively or synergistically enhance the therapeutic effect of LLL in energy-producing insufficient tissue-like injured brain. 10.1038/jcbfm.2015.87
    Effects of Hyperbaric Oxygen Therapy on Inflammasome Signaling after Traumatic Brain Injury. Geng Fengyang,Ma Yinghua,Xing Tao,Zhuang Xianbo,Zhu Jianxin,Yao Lusu Neuroimmunomodulation OBJECTIVE:Neuroinflammation plays an important role in secondary tissue damage after traumatic brain injury (TBI). Recently, the inflammasome-mediated inflammatory pathway has been observed in the inflammatory response of TBI. In this study, we investigated the influence of hyperbaric oxygen therapy (HBOT) on inflammasome activation after TBI. METHODS:The experimental mice were randomly divided into 4 groups as follows: sham-operated normobaric air (21% O2 at one absolute atmosphere), HBOT only, TBI + normobaric air and TBI + HBOT. Following the evaluation of motor deficits and brain edema, the expression of inflammasome components and effectors was measured by qRT-PCR and Western blotting. Moreover, alterations in IL-1β, IL-18 and high-mobility group box 1 (HMGB1) were calculated by enzyme-linked immunosorbent assay at each time point after injury. RESULTS:HBOT improved motor score and reduced brain edema. Furthermore, it suppressed protein expression of inflammasome components and reduced the levels of IL-1β and IL-18, accompanied by the reduction of HMGB1 in brain tissues and serum. CONCLUSION:These results suggest that HBOT may alleviate the inflammatory response after TBI by inhibiting the activation of inflammasome signaling. 10.1159/000445689
    Single-nucleotide polymorphism screening and RNA sequencing of key messenger RNAs associated with neonatal hypoxic-ischemia brain damage. Xiong Liu-Lin,Xue Lu-Lu,Al-Hawwas Mohammed,Huang Jin,Niu Rui-Ze,Tan Ya-Xin,Xu Yang,Su Ying-Ying,Liu Jia,Wang Ting-Hua Neural regeneration research A single-nucleotide polymorphism (SNP) is an alteration in one nucleotide in a certain position within a genome. SNPs are associated with disease susceptibility. However, the influences of SNPs on the pathogenesis of neonatal hypoxic-ischemic brain damage remain elusive. Seven-day-old rats were used to establish a hypoxic ischemic encephalopathy model. SNPs and expression profiles of mRNAs were analyzed in hypoxic ischemic encephalopathy model rats using RNA sequencing. Genes exhibiting SNPs associated with hypoxic ischemic encephalopathy were identified and studied by gene ontology and pathway analysis to identify their possible involvement in the disease mechanism. We identified 89 up-regulated genes containing SNPs that were mainly located on chromosome 1 and 2. Gene ontology analysis indicated that the up-regulated genes containing SNPs are mainly involved in angiogenesis, wound healing and glutamatergic synapse and biological processing of calcium-activated chloride channels. Signaling pathway analysis indicated that the differentially expressed genes play a role in glutamatergic synapses, long-term depression and oxytocin signaling. Moreover, intersection analysis of high throughput screening following PubMed retrieval and RNA sequencing for SNPs showed that CSRNP1, DUSP5 and LRRC25 were most relevant to hypoxic ischemic encephalopathy. Significant up-regulation of genes was confirmed by quantitative real-time polymerase chain reaction analysis of oxygen-glucose-deprived human fetal cortical neurons. Our results indicate that CSRNP1, DUSP5 and LRRC25, containing SNPs, may be involved in the pathogenesis of hypoxic ischemic encephalopathy. These findings indicate a novel direction for further hypoxic ischemic encephalopathy research. This animal study was approved on February 5, 2017 by the Animal Care and Use Committee of Kunming Medical University, Yunnan Province, China (approval No. kmmu2019038). Cerebral tissue collection from a human fetus was approved on September 30, 2015 by the Ethics Committee of Kunming Medical University, China (approval No. 2015-9). 10.4103/1673-5374.264469
    Protective role of wogonin following traumatic brain injury by reducing oxidative stress and apoptosis via the PI3K/Nrf2/HO‑1 pathway. Feng Yan,Ju Yaru,Yan Zhongjie,Ji Mingjun,Yang Ming,Wu Qiang,Wang Liqun,Sun Guozhu International journal of molecular medicine Traumatic brain injury (TBI) is usually caused by accidental injuries and traffic accidents, with a very high mortality rate. Treatment and management following TBI are essential to reduce patient injury and help improve long‑term prognosis. Wogonin is a flavonoid compound with an antioxidant effect extracted from Georgi. However, the function and mechanism of wogonin in protecting brain injury remain to be elucidated. The present study established a TBI model of Sprague‑Dawley rats and treated them with wogonin following trauma. The results showed that wogonin treatment significantly reduced neurobehavioral disorders, brain edema and hippocampal neuron damage caused by TBI. It was found that in TBI rats, administration of wogonin increased the levels of antioxidant factors glutathione, superoxide dismutase and catalase in the CA1 region of the hippocampus and significantly inhibited the production of malondialdehyde and reactive oxygen species. western blotting data showed that wogonin exerted antioxidant activity by downregulating the level of NOX protein. In inhibiting cell apoptosis, wogonin upregulated the expression of Bcl‑2 protein in the hippocampal CA1 region of TBI rats and inhibited caspase‑3 and Bax proteins. Additionally, wogonin inhibited the progression of injury following TBI through the PI3K/Akt/nuclear factor‑erythroid factor 2‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1) signaling pathway. Wogonin increased the expression of phosphorylated Akt, Nrf2 and HO‑1 in the hippocampus of TBI rats. Following the administration of PI3K inhibitor LY294002, the upregulation of these proteins by wogonin was partly reversed. In addition, LY294002 partially reversed the regulation of wogonin on NOX, caspase‑3, Bax and Bcl‑2 proteins. Therefore, wogonin exerts antioxidant and anti‑apoptotic properties to prevent hippocampal damage following TBI, which is accomplished through the PI3K/Akt/Nrf2/HO‑1 pathway. 10.3892/ijmm.2022.5109
    Phoenixin-14 protects human brain vascular endothelial cells against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced inflammation and permeability. Zhang Benping,Li Jiebing Archives of biochemistry and biophysics Stroke is one of the world's most deadly pathologies, and the rate of stroke recurrence is high. However, due to the complex nature of ischemia and reperfusion injury, there is presently no reliable treatment. The main factors driving brain damage from ischemic stroke are neuronal cell death resulting from oxidative stress, inflammation, and failure of the blood brain barrier. While under normal conditions, the blood brain barrier acts as a selectively permeable membrane allowing solutes and other substances to pass into the tissues of the central nervous system, ischemia and reperfusion alter the expression of tight junction proteins such as occludin, which leads to unmitigated perfusion and loss of homeostasis. Phoenixin-14 is a 14-amino acid neuropeptide that has been shown to play a role in regulating reproduction, blood sugar metabolism, pain, anxiety, and more recently, certain aspects of ischemic cardiac injury. In the present study, we found that phoenixin-14 confers protective effects against oxygen-glucose deprivation/reoxygenation (OGD/R) injury in bEnd.3 brain endothelial cells. Phoenixin-14 attenuated oxidative stress via downregulation of ROS and NOX1 and inhibited HMGB1 expression. Additionally, phoenixin-14 increased the expression of eNOS and NO, which play a protective role. Phoenixin-14 reduced endothelial monolayer permeability by increasing the expression of occludin. Finally, we found that the effects of phoenixin-14 on the expression of eNOS and occludin are dependent on the KLF2 transcriptional pathway, as evidenced by the results of our KLF2 knockdown experiment. Thus, phoenixin-14 may serve as a novel therapeutic agent for ischemic stroke. 10.1016/j.abb.2020.108275
    Resveratrol Alleviates Ischemic Brain Injury by Inhibiting the Activation of Pro-Inflammatory Microglia Via the CD147/MMP-9 Pathway. Zhang Haifang,Zhao Wenjing Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association OBJECTIVE:Ischemic stroke is one of the most common diseases with high mortality and disability. This study was intended to investigate the mechanism of resveratrol (RES) regulating microglia activation through the CD147/matrix metalloproteinase-9 (MMP-9) pathway on ischemic stroke. METHODS:The middle cerebral artery occlusion (MCAO) mouse model and oxygen and glucose deprivation (OGD) cell model were established. The behavioral defects, neuronal damage, cerebral infarction volume, and histopathological changes were assessed in MCAO mice. The activation of pro-inflammatory microglia CD86/Iba-1 and anti-inflammatory microglia CD206/Iba-1 was detected. The expressions of pro-inflammatory microglia markers (CD11b, CD16) and cytokines (TNF-α, IL-1β, and IL-6) were measured. The activation of the CD147/MMP-9 pathway was detected and its effect on microglia activation was assessed. RESULTS:After RES administration, the neuronal dysfunction, infarct volume, and morphological changes of neurons were improved in MCAO mice. Meanwhile, the motivation of pro-inflammatory microglia and the release of inflammatory factors were repressed. RES suppressed the stimulation of OGD/R microglia and the release of inflammatory factors. The expression of CD147 and MMP-9 in primary microglia was up-regulated. Inhibition of CD147 can reduce pro-inflammatory microglia activation by inhibiting MMP-9 expression. RES inhibited the CD147/MMP-9 axis in OGD/R microglia, and overexpression of CD147 partially reversed the inhibitory effect of RES on the activation and release of inflammatory factors in OGD/R microglia. CONCLUSION:RES restrained the stimulation of pro-inflammatory microglia by down-regulating the CD147/MMP-9 axis, and thus protected against ischemic brain injury. 10.1016/j.jstrokecerebrovasdis.2022.106307
    Oxygen uptake on-kinetics before and after aerobic exercise training in individuals with traumatic brain injury. Chin Lisa M K,Chan Leighton,Drinkard Bart,Keyser Randall E Disability and rehabilitation The high prevalence of fatigue among persons with traumatic brain injury (TBI) may be related to poor cardiorespiratory fitness observed in this population. Oxygen uptake on-kinetics is a method of assessing cardiorespiratory fitness and may be used to examine performance fatigability (decline in performance during a given activity) in persons with TBI. To examine the effect of aerobic exercise training on oxygen uptake on-kinetics during treadmill walking in individuals with TBI. Seven ambulatory adults with chronic non-penetrating TBI performed short moderate-intensity (3-6 metabolic equivalents) walking bouts on a treadmill, prior to and following an aerobic exercise training program (clinicaltrials.gov: NCT01294332). The 12-week training program consisted of vigorous-intensity exercise on a treadmill for 30 min, 3 times a week. Breath-by-breath pulmonary gas exchange was measured throughout the bouts, and oxygen uptake on-kinetics described the time taken to achieve a steady-state response. Faster oxygen uptake on-kinetics was observed after exercise training, for both the absolute and relative intensity as pre-training. Faster oxygen uptake on-kinetics following aerobic exercise training suggests an attenuated decline in physical performance during a standardized walking bout and improved performance fatigability in these individuals with TBI.Implications for rehabilitationSevere fatigue is a common complaint among persons with traumatic brain injury (TBI).Oxygen uptake on-kinetics may be used as an objective physiological measure of performance fatigability in persons with TBI.Faster oxygen uptake on-kinetics following aerobic exercise training suggests improved performance fatigability in these individuals with TBI.Aerobic exercise training appeared beneficial for reducing performance fatigability and may be considered as part of the rehabilitative strategy for those living with TBI. 10.1080/09638288.2018.1483432
    Physiological complexity of acute traumatic brain injury in patients treated with a brain oxygen protocol: utility of symbolic regression in predictive modeling of a dynamical system. Narotam Pradeep K,Morrison John F,Schmidt Michael D,Nathoo Narendra Journal of neurotrauma Predictive modeling of emergent behavior, inherent to complex physiological systems, requires the analysis of large complex clinical data streams currently being generated in the intensive care unit. Brain tissue oxygen protocols have yielded outcome benefits in traumatic brain injury (TBI), but the critical physiological thresholds for low brain oxygen have not been established for a dynamical patho-physiological system. High frequency, multi-modal clinical data sets from 29 patients with severe TBI who underwent multi-modality neuro-clinical care monitoring and treatment with a brain oxygen protocol were analyzed. The inter-relationship between acute physiological parameters was determined using symbolic regression (SR) as the computational framework. The mean patient age was 44.4±15 with a mean admission GCS of 6.6±3.9. Sixty-three percent sustained motor vehicle accidents and the most common pathology was intra-cerebral hemorrhage (50%). Hospital discharge mortality was 21%, poor outcome occurred in 24% of patients, and good outcome occurred in 56% of patients. Criticality for low brain oxygen was intracranial pressure (ICP) ≥22.8 mm Hg, for mortality at ICP≥37.1 mm Hg. The upper therapeutic threshold for cerebral perfusion pressure (CPP) was 75 mm Hg. Eubaric hyperoxia significantly impacted partial pressure of oxygen in brain tissue (PbtO2) at all ICP levels. Optimal brain temperature (Tbr) was 34-35°C, with an adverse effect when Tbr≥38°C. Survivors clustered at [Formula: see text] Hg vs. non-survivors [Formula: see text] 18 mm Hg. There were two mortality clusters for ICP: High ICP/low PbtO2 and low ICP/low PbtO2. Survivors maintained PbtO2 at all ranges of mean arterial pressure in contrast to non-survivors. The final SR equation for cerebral oxygenation is: [Formula: see text]. The SR-model of acute TBI advances new physiological thresholds or boundary conditions for acute TBI management: PbtO2≥25 mmHg; ICP≤22 mmHg; CPP≈60-75 mmHg; and Tbr≈34-37°C. SR is congruous with the emerging field of complexity science in the modeling of dynamical physiological systems, especially during pathophysiological states. The SR model of TBI is generalizable to known physical laws. This increase in entropy reduces uncertainty and improves predictive capacity. SR is an appropriate computational framework to enable future smart monitoring devices. 10.1089/neu.2013.3104
    Electroencephalographic Periodic Discharges and Frequency-Dependent Brain Tissue Hypoxia in Acute Brain Injury. Witsch Jens,Frey Hans-Peter,Schmidt J Michael,Velazquez Angela,Falo Cristina M,Reznik Michael,Roh David,Agarwal Sachin,Park Soojin,Connolly E Sander,Claassen Jan JAMA neurology Importance:Periodic discharges (PDs) that do not meet seizure criteria, also termed the ictal interictal continuum, are pervasive on electroencephalographic (EEG) recordings after acute brain injury. However, their association with brain homeostasis and the need for clinical intervention remain unknown. Objective:To determine whether distinct PD patterns can be identified that, similar to electrographic seizures, cause brain tissue hypoxia, a measure of ongoing brain injury. Design, Setting, and Participants:This prospective cohort study included 90 comatose patients with high-grade spontaneous subarachnoid hemorrhage who underwent continuous surface (scalp) EEG (sEEG) recording and multimodality monitoring, including invasive measurements of intracortical (depth) EEG (dEEG), partial pressure of oxygen in interstitial brain tissue (Pbto2), and regional cerebral blood flow (CBF). Patient data were collected from June 1, 2006, to September 1, 2014, at a single tertiary care center. The retrospective analysis was performed from September 1, 2014, to May 1, 2016, with a hypothesis that the effect on brain tissue oxygenation was primarily dependent on the discharge frequency. Main Outcomes and Measures:Electroencephalographic recordings were visually classified based on PD frequency and spatial distribution of discharges. Correlations between mean multimodality monitoring data and change-point analyses were performed to characterize electrophysiological changes by applying bootstrapping. Results:Of the 90 patients included in the study (26 men and 64 women; mean [SD] age, 55 [15] years), 32 (36%) had PDs on sEEG and dEEG recordings and 21 (23%) on dEEG recordings only. Frequencies of PDs ranged from 0.5 to 2.5 Hz. Median Pbto2 was 23 mm Hg without PDs compared with 16 mm Hg at 2.0 Hz and 14 mm Hg at 2.5 Hz (differences were significant for 0 vs 2.5 Hz based on bootstrapping). Change-point analysis confirmed a temporal association of high-frequency PD onset (≥2.0 Hz) and Pbto2 reduction (median normalized Pbto2 decreased by 25% 5-10 minutes after onset). Increased regional CBF of 21.0 mL/100 g/min for 0 Hz, 25.9 mL/100 g/min for 1.0 Hz, 27.5 mL/100 g/min for 1.5 Hz, and 34.7 mL/100 g/min for 2.0 Hz and increased global cerebral perfusion pressure of 91 mm Hg for 0 Hz, 100.5 mm Hg for 0.5 Hz, 95.5 mm Hg for 1.0 Hz, 97.0 mm Hg for 2.0 Hz, 98.0 mm Hg for 2.5 Hz, 95.0 mm Hg for 2.5 Hz, and 67.8 mm Hg for 3.0 Hz were seen for higher PD frequencies. Conclusions and Relevance:These data give some support to consider redefining the continuum between seizures and PDs, suggesting that additional damage after acute brain injury may be reflected by frequency changes in electrocerebral recordings. Similar to seizures, cerebral blood flow increases in patients with PDs to compensate for the increased metabolic demand but higher-frequency PDs (>2 per second) may be inadequately compensated without an additional rise in CBF and associated with brain tissue hypoxia, or higher-frequency PDs may reflect inadequacies in brain compensatory mechanisms. 10.1001/jamaneurol.2016.5325
    Factors Associated With Brain Tissue Oxygenation Changes After RBC Transfusion in Acute Brain Injury Patients. Critical care medicine OBJECTIVES:Anemia is common after acute brain injury and can be associated with brain tissue hypoxia. RBC transfusion (RBCT) can improve brain oxygenation; however, predictors of such improvement remain unknown. We aimed to identify the factors associated with PbtO2 increase (greater than 20% from baseline value) after RBCT, using a generalized mixed model. DESIGN:This is a multicentric retrospective cohort study (2012-2020). SETTING:This study was conducted in three European ICUs of University Hospitals located in Belgium, Switzerland, and Austria. PATIENTS:All patients with acute brain injury who were monitored with brain tissue oxygenation (PbtO2) catheters and received at least one RBCT. INTERVENTION:Patients received at least one RBCT. PbtO2 was recorded before, 1 hour, and 2 hours after RBCT. MEASUREMENTS AND MAIN RESULTS:We included 69 patients receiving a total of 109 RBCTs after a median of 9 days (5-13 d) after injury. Baseline hemoglobin (Hb) and PbtO2 were 7.9 g/dL [7.3-8.7 g/dL] and 21 mm Hg (16-26 mm Hg), respectively; 2 hours after RBCT, the median absolute Hb and PbtO2 increases from baseline were 1.2 g/dL [0.8-1.8 g/dL] (p = 0.001) and 3 mm Hg (0-6 mm Hg) (p = 0.001). A 20% increase in PbtO2 after RBCT was observed in 45 transfusions (41%). High heart rate (HR) and low PbtO2 at baseline were independently associated with a 20% increase in PbtO2 after RBCT. Baseline PbtO2 had an area under receiver operator characteristic of 0.73 (95% CI, 0.64-0.83) to predict PbtO2 increase; a PbtO2 of 20 mm Hg had a sensitivity of 58% and a specificity of 73% to predict PbtO2 increase after RBCT. CONCLUSIONS:Lower PbtO2 values and high HR at baseline could predict a significant increase in brain oxygenation after RBCT. 10.1097/CCM.0000000000005460
    NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage. Casas Ana I,Geuss Eva,Kleikers Pamela W M,Mencl Stine,Herrmann Alexander M,Buendia Izaskun,Egea Javier,Meuth Sven G,Lopez Manuela G,Kleinschnitz Christoph,Schmidt Harald H H W Proceedings of the National Academy of Sciences of the United States of America Ischemic injury represents the most frequent cause of death and disability, and it remains unclear why, of all body organs, the brain is most sensitive to hypoxia. In many tissues, type 4 NADPH oxidase is induced upon ischemia or hypoxia, converting oxygen to reactive oxygen species. Here, we show in mouse models of ischemia in the heart, brain, and hindlimb that only in the brain does NADPH oxidase 4 (NOX4) lead to ischemic damage. We explain this distinct cellular distribution pattern through cell-specific knockouts. Endothelial NOX4 breaks down the BBB, while neuronal NOX4 leads to neuronal autotoxicity. Vascular smooth muscle NOX4, the common denominator of ischemia within all ischemic organs, played no apparent role. The direct neuroprotective potential of pharmacological NOX4 inhibition was confirmed in an ex vivo model, free of vascular and BBB components. Our results demonstrate that the heightened sensitivity of the brain to ischemic damage is due to an organ-specific role of NOX4 in blood-brain-barrier endothelial cells and neurons. This mechanism is conserved in at least two rodents and humans, making NOX4 a prime target for a first-in-class mechanism-based, cytoprotective therapy in the unmet high medical need indication of ischemic stroke. 10.1073/pnas.1705034114
    Hierarchical Cluster Analysis Identifies Distinct Physiological States After Acute Brain Injury. Neurocritical care BACKGROUND:Analysis of intracranial multimodality monitoring data is challenging, and quantitative methods may help identify unique physiological signatures that inform therapeutic strategies and outcome prediction. The aim of this study was to test the hypothesis that data-driven approaches can identify distinct physiological states from intracranial multimodality monitoring data. METHODS:This was a single-center retrospective observational study of patients with either severe traumatic brain injury or high-grade subarachnoid hemorrhage who underwent invasive multimodality neuromonitoring. We used hierarchical cluster analysis to group hourly values for heart rate, mean arterial pressure, intracranial pressure, brain tissue oxygen, and cerebral microdialysis across all included patients into distinct groups. Average values for measured physiological variables were compared across the identified clusters, and physiological profiles from identified clusters were mapped onto physiological states known to occur after acute brain injury. The distribution of clusters was compared between patients with favorable outcome (discharged to home or acute rehab) and unfavorable outcome (in-hospital death or discharged to chronic nursing facility). RESULTS:A total of 1704 observations from 20 patients were included. Even though the difference in mean values for measured variables between patients with favorable and unfavorable outcome were small, we identified four distinct clusters within our data: (1) events with low brain tissue oxygen and high lactate-to-pyruvate ratio-values (consistent with cerebral ischemia), (2) events with higher intracranial pressure values without evidence for ischemia (3) events which appeared to be physiologically "normal," and (4) events with high cerebral lactate without brain hypoxia (consistent with cerebral hyperglycolysis). Patients with a favorable outcome had a greater proportion of cluster 3 (normal) events, whereas patients with an unfavorable outcome had a greater proportion of cluster 1 (ischemia) and cluster 4 (hyperglycolysis) events (p < 0.0001, Fisher-Freeman-Halton test). CONCLUSIONS:A data-driven approach can identify distinct groupings from invasive multimodality neuromonitoring data that may have implications for therapeutic strategies and outcome predictions. These groupings could be used as classifiers to train machine learning models that can aid in the treatment of patients with acute brain injury. Further work is needed to replicate the findings of this exploratory study in larger data sets. 10.1007/s12028-021-01362-6
    A model of metabolic supply-demand mismatch leading to secondary brain injury. Journal of neurophysiology Secondary brain injury (SBI) is defined as new or worsening injury to the brain after an initial neurologic insult, such as hemorrhage, trauma, ischemic stroke, or infection. It is a common and potentially preventable complication following many types of primary brain injury (PBI). However, mechanistic details about how PBI leads to additional brain injury and evolves into SBI are poorly characterized. In this work, we propose a mechanistic model for the metabolic supply demand mismatch hypothesis (MSDMH) of SBI. Our model, based on the Hodgkin-Huxley model, supplemented with additional dynamics for extracellular potassium, oxygen concentration, and excitotoxity, provides a high-level unified explanation for why patients with acute brain injury frequently develop SBI. We investigate how decreased oxygen, increased extracellular potassium, excitotoxicity, and seizures can induce SBI and suggest three underlying paths for how events following PBI may lead to SBI. The proposed model also helps explain several important empirical observations, including the common association of acute brain injury with seizures, the association of seizures with tissue hypoxia and so on. In contrast to current practices which assume that ischemia plays the predominant role in SBI, our model suggests that metabolic crisis involved in SBI can also be nonischemic. Our findings offer a more comprehensive understanding of the complex interrelationship among potassium, oxygen, excitotoxicity, seizures, and SBI. We present a novel mechanistic model for the metabolic supply demand mismatch hypothesis (MSDMH), which attempts to explain why patients with acute brain injury frequently develop seizure activity and secondary brain injury (SBI). Specifically, we investigate how decreased oxygen, increased extracellular potassium, excitotoxicity, seizures, all common sequalae of primary brain injury (PBI), can induce SBI and suggest three underlying paths for how events following PBI may lead to SBI. 10.1152/jn.00674.2020
    T3 alleviates neuroinflammation and reduces early brain injury after subarachnoid haemorrhage by promoting mitophagy via PINK 1-parkin pathway. Experimental neurology Subarachnoid haemorrhage (SAH) is a common and devastating complication of haemorrhagic stroke. SAH is characterised by high mortality rates, permanent disabilities, and is often caused by the rupture of intracranial aneurysms. Low serum triiodothyronine (T3) concentrations have been associated with severe SAH and poor prognosis. T3 has been previously described as an inhibitor of lung fibrosis, and it acts by stimulating autophagy and mitophagy. Here, we indicated in vitro that T3 treatment suppressed neuronal apoptosis by reducing the release of mitochondrial reactive oxygen species (ROS), leading to mitochondrial membrane potential (MMP) decrease. Moreover, this preventative effect was reversed by PINK 1-siRNA treatment. We showed that in vivo T3 treatment promoted mitophagy, decreased microglial activation, alleviated neuroinflammation, and reduced neuronal apoptosis following SAH. Overall, this thyroid hormone (TH) exerts a protective effect on neurones after SAH via the PINK 1/PARKIN pathway. Considering the protective function of TH against neuronal damage, further research can establish TH treatment as a promising and effective therapeutic option for early brain injury (EBI) after SAH. 10.1016/j.expneurol.2022.114175
    Effect of coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats. Kalayci Murat,Unal Mufit M,Gul Sanser,Acikgoz Serefden,Kandemir Nilufer,Hanci Volkan,Edebali Nurullah,Acikgoz Bektas BMC neuroscience BACKGROUND:Head trauma is one of the most important clinical issues that not only can be fatal and disabling, requiring long-term treatment and care, but also can cause heavy financial burden. Formation or distribution of free oxygen radicals should be decreased to enable fixing of poor neurological outcomes and to prevent neuronal damage secondary to ischemia after trauma. Coenzyme Q₁₀ (CoQ₁₀), a component of the mitochondrial electron transport chain, is a strong antioxidant that plays a role in membrane stabilization. In this study, the role of CoQ₁₀ in the treatment of head trauma is researched by analyzing the histopathological and biochemical effects of CoQ₁₀ administered after experimental traumatic brain injury in rats. A traumatic brain-injury model was created in all rats. Trauma was inflicted on rats by the free fall of an object of 450 g weight from a height of 70 cm on the frontoparietal midline onto a metal disc fixed between the coronal and the lambdoid sutures after a midline incision was carried out. RESULTS:In the biochemical tests, tissue malondialdehyde (MDA) levels were significantly higher in the traumatic brain-injury group compared to the sham group (p < 0.05). Administration of CoQ₁₀ after trauma was shown to be protective because it significantly lowered the increased MDA levels (p < 0.05). Comparing the superoxide dismutase (SOD) levels of the four groups, trauma + CoQ₁₀ group had SOD levels ranging between those of sham group and traumatic brain-injury group, and no statistically significant increase was detected. Histopathological results showed a statistically significant difference between the CoQ₁₀ and the other trauma-subjected groups with reference to vascular congestion, neuronal loss, nuclear pyknosis, nuclear hyperchromasia, cytoplasmic eosinophilia, and axonal edema (p < 0.05). CONCLUSION:Neuronal degenerative findings and the secondary brain damage and ischemia caused by oxidative stress are decreased by CoQ₁₀ use in rats with traumatic brain injury. 10.1186/1471-2202-12-75
    Brain Tissue Oxygen and Cerebrovascular Reactivity in Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Exploratory Analysis of Insult Burden. Zeiler Frederick A,Beqiri Erta,Cabeleira Manuel,Hutchinson Peter J,Stocchetti Nino,Menon David K,Czosnyka Marek,Smielewski Peter,Ercole Ari, Journal of neurotrauma Pressure reactivity index (PRx) and brain tissue oxygen (PbtO) are associated with outcome in traumatic brain injury (TBI). This study explores the relationship between PRx and PbtO in adult moderate/severe TBI. Using the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) high resolution intensive care unit (ICU) sub-study cohort, we evaluated those patients with archived high-frequency digital intraparenchymal intracranial pressure (ICP) and PbtO monitoring data of, a minimum of 6 h in duration, and the presence of a 6 month Glasgow Outcome Scale -Extended (GOSE) score. Digital physiological signals were processed for ICP, PbtO, and PRx, with the % time above/below defined thresholds determined. The duration of ICP, PbtO, and PRx derangements was characterized. Associations with dichotomized 6-month GOSE (alive/dead, and favorable/unfavorable outcome; ≤ 4 = unfavorable), were assessed. A total of 43 patients were included. Severely impaired cerebrovascular reactivity was seen during elevated ICP and low PbtO episodes. However, most of the acute ICU physiological derangements were impaired cerebrovascular reactivity, not ICP elevations or low PbtO episodes. Low PbtO without PRx impairment was rarely seen. % time spent above PRx threshold was associated with mortality at 6 months for thresholds of 0 (area under the curve [AUC] 0.734,  = 0.003), > +0.25 (AUC 0.747,  = 0.002) and > +0.35 (AUC 0.745,  = 0.002). Similar relationships were not seen for % time with ICP >20 mm Hg, and PbtO < 20 mm Hg in this cohort. Extreme impairment in cerebrovascular reactivity is seen during concurrent episodes of elevated ICP and low PbtO. However, the majority of the deranged cerebral physiology seen during the acute ICU phase is impairment in cerebrovascular reactivity, with most impairment occurring in the presence of normal PbtO levels. Measures of cerebrovascular reactivity appear to display the most consistent associations with global outcome in TBI, compared with ICP and PbtO. 10.1089/neu.2020.7024
    Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury. Hoeber Daniela,Sifringer Marco,van de Looij Yohan,Herz Josephine,Sizonenko Stéphane V,Kempe Karina,Serdar Meray,Palasz Joanna,Hadamitzky Martin,Endesfelder Stefanie,Fandrey Joachim,Felderhoff-Müser Ursula,Bendix Ivo Oxidative medicine and cellular longevity Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg) at the onset of hyperoxia (24 hours, 80% oxygen) in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity. 10.1155/2016/9247493
    Core-Cross-Linked Nanoparticles Reduce Neuroinflammation and Improve Outcome in a Mouse Model of Traumatic Brain Injury. Yoo Dasom,Magsam Alexander W,Kelly Abby M,Stayton Patrick S,Kievit Forrest M,Convertine Anthony J ACS nano Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults, yet there are currently no treatments available that prevent the secondary spread of damage beyond the initial insult. The chronic progression of this secondary injury is in part caused by the release of reactive oxygen species (ROS) into surrounding normal brain. Thus, treatments that can enter the brain and reduce the spread of ROS should improve outcome from TBI. Here a highly versatile, reproducible, and scalable method to synthesize core-cross-linked nanoparticles (NPs) from polysorbate 80 (PS80) using a combination of thiol-ene and thiol-Michael chemistry is described. The resultant NPs consist of a ROS-reactive thioether cross-linked core stabilized in aqueous solution by hydroxy-functional oligoethylene oxide segments. These NPs show narrow molecular weight distributions and have a high proportion of thioether units that reduce local levels of ROS. In a controlled cortical impact mouse model of TBI, the NPs are able to rapidly accumulate and be retained in damaged brain as visualized through fluorescence imaging, reduce neuroinflammation and the secondary spread of injury as determined through magnetic resonance imaging and histopathology, and improve functional outcome as determined through behavioral analyses. Our findings provide strong evidence that these NPs may, upon further development and testing, provide a useful strategy to help improve the outcome of patients following a TBI. 10.1021/acsnano.7b03426
    Brain oxidative damage in murine models of neonatal hypoxia/ischemia and reoxygenation. Torres-Cuevas Isabel,Corral-Debrinski Marisol,Gressens Pierre Free radical biology & medicine The brain is one of the main organs affected by hypoxia and reoxygenation in the neonatal period and one of the most vulnerable to oxidative stress. Hypoxia/ischemia and reoxygenation leads to impairment of neurogenesis, disruption of cortical migration, mitochondrial damage and neuroinflammation. The extent of the injury depends on the clinical manifestation in the affected regions. Preterm newborns are highly vulnerable, and they exhibit severe clinical manifestations such as intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP) and diffuse white matter injury (DWMI) among others. In the neonatal period, the accumulation of high levels of reactive oxygen species exacerbated by the immature antioxidant defense systems in represents cellular threats that, if they exceed or bypass physiological counteracting mechanisms, are responsible of significant neuronal damage. Several experimental models in mice mimic the consequences of perinatal asphyxia and the use of oxygen in the reanimation process that produce brain injury. The aim of this review is to highlight brain damage associated with oxidative stress in different murine models of hypoxia/ischemia and reoxygenation. 10.1016/j.freeradbiomed.2019.06.011
    Supplemental oxygen for traumatic brain injury: A systematic review. Hansen Thea Ellehammer,Christensen Rasmus Ejlersgaard,Baekgaard Josefine,Steinmetz Jacob,Rasmussen Lars S Acta anaesthesiologica Scandinavica BACKGROUND:Oxygen supplementation is recommended after traumatic brain injury (TBI) but excessive oxygen may be harmful. The aim of this study was to investigate the effect of supplemental oxygen or high/low inspiratory oxygen fraction (FiO ) for TBI patients on in-hospital mortality. METHODS:We searched Medline (Pubmed), EMBASE and the Cochrane Library for interventional and observational studies fulfilling the following criteria: TBI patients >17 years (population); initial use of supplemental oxygen/high (≥0.6) FiO (intervention) vs no supplemental oxygen/low (<0.6) FiO (control) for spontaneously breathing or mechanically ventilated TBI patients, respectively with in-hospital mortality as primary outcome. Secondary outcomes were 30-day and 1-year mortality, length of stay in hospital or intensive care unit, days on mechanical ventilation, complications, and neurological impairment. RESULTS:We screened 4846 citations. Two interventional studies comparing high vs low FiO for mechanically ventilated TBI patients were included. No difference in in-hospital mortality was found. The first study found a statistically significant shorter length of stay in the intensive care unit for the high FiO -group (6.5 [4.6-11.4] vs. 11.4 [5.8-17.2] days, p = 0.02). The second study found a lower disability at 6 months in the high FiO -group with low disability in 25 (73.5%) vs. 15 (44.1%), moderate disability in 9 (26.5%) vs. 16 (47.1%), and severe disability in 0 (0.0%) vs. 3 (8.8%), p = 0.02. CONCLUSION:Evidence on the effect of initial use of high/low FiO for TBI patients on in-hospital mortality was extremely limited. Evidence on the use of supplemental oxygen for spontaneously breathing TBI patients is lacking. 10.1111/aas.14019
    A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Chesnut Randall,Aguilera Sergio,Buki Andras,Bulger Eileen,Citerio Giuseppe,Cooper D Jamie,Arrastia Ramon Diaz,Diringer Michael,Figaji Anthony,Gao Guoyi,Geocadin Romer,Ghajar Jamshid,Harris Odette,Hoffer Alan,Hutchinson Peter,Joseph Mathew,Kitagawa Ryan,Manley Geoffrey,Mayer Stephan,Menon David K,Meyfroidt Geert,Michael Daniel B,Oddo Mauro,Okonkwo David,Patel Mayur,Robertson Claudia,Rosenfeld Jeffrey V,Rubiano Andres M,Sahuquillo Juan,Servadei Franco,Shutter Lori,Stein Deborah,Stocchetti Nino,Taccone Fabio Silvio,Timmons Shelly,Tsai Eve,Ullman Jamie S,Vespa Paul,Videtta Walter,Wright David W,Zammit Christopher,Hawryluk Gregory W J Intensive care medicine BACKGROUND:Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. METHODS:Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. RESULTS:We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms. CONCLUSIONS:These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference. 10.1007/s00134-019-05900-x
    Irisin Rescues Blood-Brain Barrier Permeability following Traumatic Brain Injury and Contributes to the Neuroprotection of Exercise in Traumatic Brain Injury. Guo Peipei,Jin Zhao,Wang Jin,Sang Aming,Wu Huisheng Oxidative medicine and cellular longevity Traumatic brain injury (TBI) has a high incidence, mortality, and morbidity all over the world. One important reason for its poor clinical prognosis is brain edema caused by blood-brain barrier (BBB) dysfunction after TBI. The mechanism may be related to the disorder of mitochondrial morphology and function of neurons in damaged brain tissue, the decrease of uncoupling protein 2 (UCP2) activity, and the increase of inflammatory reaction and oxidative stress. In this study, we aimed to investigate the effects of exogenous irisin on BBB dysfunction after TBI and its role in the neuroprotective effects of endurance exercise (EE) in mice. The concentrations of irisin in cerebrospinal fluid (CSF) and plasma of patients with mild to severe TBI were measured by ELISA. Then, male C57BL/6J mice and UCP2 knockout mice with C57BL/6J background were used to establish the TBI model. The BBB structure and permeability were examined by transmission electron microscopy and Evans blue extravasation, respectively. The protein expressions of irisin, occludin, claudin-5, zonula occludens-1 (ZO-1), nuclear factor E2-related factor 2(Nrf2), quinine oxidoreductase (NQO-1), hemeoxygenase-1 (HO-1), cytochrome C (Cyt-C), cytochrome C oxidase (COX IV), BCL2-associated X protein (Bax), cleaved caspase-3, and UCP2 were detected by western blot. The production of reactive oxygen species (ROS) was evaluated by the dihydroethidium (DHE) staining. The levels of inflammatory factors were detected by ELISA. In this study, we found that the CSF irisin levels were positively correlated with the severity of disease in patients with TBI and both EE and exogenous irisin could reduce BBB damage in a mouse model of TBI. In addition, we used UCP2 mice and further found that irisin could improve the dysfunction of BBB after TBI by promoting the expression of UCP2 on the mitochondrial membrane of neurons, reducing the damage of mitochondrial structure and function, thus alleviating the inflammatory response and oxidative stress. In conclusion, the results of this study suggested that irisin might alleviate brain edema after TBI by promoting the expression of UCP2 on the mitochondrial membrane of neurons and contribute to the neuroprotection of EE against TBI. 10.1155/2021/1118981
    Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. Imai Kenji,Kotani Tomomi,Tsuda Hiroyuki,Mano Yukio,Nakano Tomoko,Ushida Takafumi,Li Hua,Miki Rika,Sumigama Seiji,Iwase Akira,Hirakawa Akihiro,Ohno Kinji,Toyokuni Shinya,Takeuchi Hideyuki,Mizuno Tetsuya,Suzumura Akio,Kikkawa Fumitaka Free radical biology & medicine Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H2, involved in the process of activating microglia. These results suggested that H2 holds promise for the prevention of inflammation related to perinatal brain injury. 10.1016/j.freeradbiomed.2015.12.015
    Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction. de Sousa Mirta Mittelstedt Leal,Ye Jing,Luna Luisa,Hildrestrand Gunn,Bjørås Karine,Scheffler Katja,Bjørås Magnar International journal of molecular sciences The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders. 10.3390/ijms222312924
    Ulinastatin alleviates early brain injury after intracerebral hemorrhage by inhibiting oxidative stress and neuroinflammation via ROS/MAPK/Nrf2 signaling pathway. Acta cirurgica brasileira PURPOSE:Spontaneous intracerebral hemorrhage (ICH) is still a major public health problem, with high mortality and disability. Ulinastatin (UTI) was purified from human urine and has been reported to be anti-inflammatory, organ protective, and antioxidative stress. However, the neuroprotection of UTI in ICH has not been confirmed, and the potential mechanism is unclear. In the present study, we aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in ICH-induced early brain injury in a C57BL/6 mouse model. METHODS:The neurological score, brain water content, neuroinflammatory cytokine levels, oxidative stress levels, and neuronal damage were evaluated. RESULTS:UTI treatment markedly increased the neurological score, alleviated brain edema, decreased the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and NF-κB, decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and upregulated the levels of glutathione (GSH), superoxide dismutase (SOD), and Nrf2. This finding indicated that UTI-mediated inhibition of neuroinflammation and oxidative stress alleviated neuronal damage after ICH. The neuroprotective capacity of UTI is partly dependent on the ROS/MAPK/Nrf2 signaling pathway. CONCLUSIONS:UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation and oxidative stress. 10.1590/acb370606
    Normobaric hyperoxia is associated with increased cerebral excitotoxicity after severe traumatic brain injury. Quintard Hervé,Patet Camille,Suys Tamarah,Marques-Vidal Pedro,Oddo Mauro Neurocritical care BACKGROUND:Normobaric oxygen therapy is frequently applied in neurocritical care, however, whether supplemental FiO2 has beneficial cerebral effects is still controversial. We examined in patients with severe traumatic brain injury (TBI) the effect of incremental FiO2 on cerebral excitotoxicity, quantified by cerebral microdialysis (CMD) glutamate. METHODS:This was a retrospective analysis of a database of severe TBI patients monitored with CMD and brain tissue oxygen (PbtO2). The relationship of FiO2--categorized into four separate ranges (<40, 41-60, 61-80, and >80 %)--with CMD glutamate was examined using ANOVA with Tukey's post hoc test. RESULTS:A total of 1,130 CMD samples from 36 patients--monitored for a median of 4 days--were examined. After adjusting for brain (PbtO2, intracranial pressure, cerebral perfusion pressure, lactate/pyruvate ratio, Marshall CT score) and systemic (PaCO2, PaO2, hemoglobin, APACHE score) covariates, high FiO2 was associated with a progressive increase in CMD glutamate [8.8 (95 % confidence interval 7.4-10.2) µmol/L at FiO2 < 40 % vs. 12.8 (10.9-14.7) µmol/L at 41-60 % FiO2, 19.3 (15.6-23) µmol/L at 61-80 % FiO2, and 22.6 (16.7-28.5) µmol/L at FiO2 > 80 %; multivariate-adjusted p < 0.05]. The threshold of FiO2-related increase in CMD glutamate was lower for samples with normal versus low PbtO2 < 20 mmHg (FiO2 > 40 % vs. FiO2 > 60 %). Hyperoxia (PaO2 > 150 mmHg) was also associated with increased CMD glutamate (adjusted p < 0.001). CONCLUSIONS:Incremental normobaric FiO2 levels were associated with increased cerebral excitotoxicity in patients with severe TBI, independent from PbtO2 and other important cerebral and systemic determinants. These data suggest that supra-normal oxygen may aggravate secondary brain damage after severe TBI. 10.1007/s12028-014-0062-0
    Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage‑induced brain injury via necroptosis and neuroinflammation. Yang Lixiang,Wang Yue,Zhang Can,Chen Tao,Cheng Huilin Molecular medicine reports Spontaneous intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity due to the lack of effective therapies. The alpha‑amino‑3‑hydroxy‑5‑methyl‑4‑isoxazolepropionic acid receptor antagonist perampanel has been reported to alleviate early brain injury following subarachnoid hemorrhage and traumatic brain injury by reducing reactive oxygen species, apoptosis, autophagy, and necroptosis. Necroptosis is a caspase‑independent programmed cell death mechanism that serves a vital role in neuronal cell death following ICH. However, the precise role of necroptosis in perampanel‑mediated neuroprotection following ICH has not been confirmed. The present study aimed to investigate the neuroprotective effects and potential molecular mechanisms of perampanel in ICH‑induced early brain injury by regulating neural necroptosis in C57BL/6 mice and in a hemin‑induced neuron damage cell culture model. Mortality, neurological score, brain water content, and neuronal death were evaluated. The results demonstrated that perampanel treatment increased the survival rate and neurological score, and increased neuron survival. In addition, perampanel treatment downregulated the protein expression levels of receptor interacting serine/threonine kinase (RIP) 1, RIP3, and mixed lineage kinase domain like pseudokinase, and of the cytokines IL‑1β, IL‑6, TNF‑α, and NF‑κB. These results indicated that perampanel‑mediated inhibition of necroptosis and neuroinflammation ameliorated neuronal death and following ICH. The neuroprotective capacity of perampanel was partly dependent on the PTEN pathway. Taken together, the results of the present study demonstrated that perampanel improved neurological outcomes in mice and reduced neuronal death by protecting against neural necroptosis and neuroinflammation. 10.3892/mmr.2021.12183
    Mechanism of Baicalein in Brain Injury After Intracerebral Hemorrhage by Inhibiting the ROS/NLRP3 Inflammasome Pathway. Inflammation Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high disability/mortality. Baicalein has strong anti-inflammatory activity. This study aims to explore the mechanism of baicalein on brain injury after ICH. The model of brain injury after ICH was established by collagenase induction, followed by the evaluation of neurological severity, brain water content, the degenerated neurons, neuronal apoptosis, and reactive oxygen species (ROS). The ICH model was treated with baicalein or silencing NLRP3 to detect brain injury. The expression of NLRP3 inflammasome was detected after treatment with ROS scavenger. The expressions of oxidative stress markers and inflammatory factors were detected, and the levels of components in NLRP3 inflammasome were detected. Baicalein reduced the damage of nervous system, lesion surface, brain water content, and apoptosis. Baicalein inhibited malondialdehyde and increased IL-10 by inhibiting ROS in brain tissue after ICH. Baicalein inhibited the high expression of NLRP3 inflammasome in ICH. ROS scavenger inhibited the NLRP3 inflammatory response by inhibiting ROS levels. Silencing NLRP3 alleviated the brain injury after ICH by inhibiting excessive oxidative stress and inflammatory factors. Overall, baicalein alleviated the brain injury after ICH by inhibiting ROS and NLRP3 inflammasome. 10.1007/s10753-021-01569-x
    Mitochondrial oxidative stress-induced transcript variants of ATF3 mediate lipotoxic brain microvascular injury. Nyunt Tun,Britton Monica,Wanichthanarak Kwanjeera,Budamagunta Madhu,Voss John C,Wilson Dennis W,Rutledge John C,Aung Hnin H Free radical biology & medicine Elevation of blood triglycerides, primarily triglyceride-rich lipoproteins (TGRL), is an independent risk factor for cardiovascular disease and vascular dementia (VaD). Accumulating evidence indicates that both atherosclerosis and VaD are linked to vascular inflammation. However, the role of TGRL in vascular inflammation, which increases risk for VaD, remains largely unknown and its underlying mechanisms are still unclear. We strived to determine the effects of postprandial TGRL exposure on brain microvascular endothelial cells, the potential risk factor of vascular inflammation, resulting in VaD. We showed in Aung et al., J Lipid Res., 2016 that postprandial TGRL lipolysis products (TL) activate mitochondrial reactive oxygen species (ROS) and increase the expression of the stress-responsive protein, activating transcription factor 3 (ATF3), which injures human brain microvascular endothelial cells (HBMECs) in vitro. In this study, we deployed high-throughput sequencing (HTS)-based RNA sequencing methods and mito stress and glycolytic rate assays with an Agilent Seahorse XF analyzer and profiled the differential expression of transcripts, constructed signaling pathways, and measured mitochondrial respiration, ATP production, proton leak, and glycolysis of HBMECs treated with TL. Conclusions: TL potentiate ROS by mitochondria which activate mitochondrial oxidative stress, decrease ATP production, increase mitochondrial proton leak and glycolysis rate, and mitochondria DNA damage. Additionally, CPT1A1 siRNA knockdown suppresses oxidative stress and prevents mitochondrial dysfunction and vascular inflammation in TL treated HBMECs. TL activates ATF3-MAPKinase, TNF, and NRF2 signaling pathways. Furthermore, the NRF2 signaling pathway which is upstream of the ATF3-MAPKinase signaling pathway, is also regulated by the mitochondrial oxidative stress. We are the first to report differential inflammatory characteristics of transcript variants 4 (ATF3-T4) and 5 (ATF3-T5) of the stress responsive gene ATF3 in HBMECs induced by postprandial TL. Specifically, our data indicates that ATF3-T4 predominantly regulates the TL-induced brain microvascular inflammation and TNF signaling. Both siRNAs of ATF3-T4 and ATF3-T5 suppress cells apoptosis and lipotoxic brain microvascular endothelial cells. These novel signaling pathways triggered by oxidative stress-responsive transcript variants, ATF3-T4 and ATF3-T5, in the brain microvascular inflammation induced by TGRL lipolysis products may contribute to pathophysiological processes of vascular dementia. 10.1016/j.freeradbiomed.2019.07.024
    RIP3 participates in early brain injury after experimental subarachnoid hemorrhage in rats by inducing necroptosis. Yuan Shuai,Yu Zhengquan,Zhang Zhuwei,Zhang Juyi,Zhang Peng,Li Xiang,Li Haiying,Shen Haitao,Chen Gang Neurobiology of disease Necroptosis is a regulated form of necrosis that is mediated by a variety of proteins including tumor necrosis factor-α (TNF-α) and receptor-interacting proteins (RIPs). TNF-α, a critical inflammatory molecule, is one of the initiating signals in the necroptosis pathway, and RIP3 acts as a switch that commits the cell to necroptosis. Subarachnoid hemorrhage (SAH) is a common type of hemorrhagic stroke with high mortality and disability rates. RIP3 has been studied in many central nervous system (CNS) diseases, but its role in SAH has not been investigated in depth. Here, we used an autologous-blood injection model to study the role of RIP3 in brain injury induced by SAH in rats. Several indexes such as brain edema, loss of blood-brain barrier (BBB) integrity, and behavioral tests of neurological function were used to evaluate brain damage in SAH-injured rats. We found that the expression of RIP3 was increased in the rat brain after SAH, reaching the highest point 24 h post-injury. We also showed that genetic or pharmacological inhibition of RIP3 or TNF-α reduced the brain damage induced by SAH, whereas overexpression of RIP3 aggravated brain injury and neurological damage. Additionally, we verified the presence of RIP3-mediated necroptosis in an in vitro SAH model of primary cultured neurons treated with conditioned medium from primary microglia activated by oxygen hemoglobin (OxyHb). Collectively, our findings indicated that RIP3 contributed to brain damage after SAH by inducing necroptosis. 10.1016/j.nbd.2019.05.004
    Safflor Yellow B Attenuates Ischemic Brain Injury via Downregulation of Long Noncoding AK046177 and Inhibition of MicroRNA-134 Expression in Rats. Wang Chaoyun,Wan Hongzhi,Wang Qiaoyun,Sun Hongliu,Sun Yeying,Wang Kexin,Zhang Chunxiang Oxidative medicine and cellular longevity Stroke breaks the oxidative balance in the body and causes extra reactive oxygen species (ROS) generation, leading to oxidative stress damage. Long noncoding RNAs (lncRNAs) and microRNAs play pivotal roles in oxidative stress-mediated brain injury. Safflor yellow B (SYB) was able to effectively reduce ischemia-mediated brain damage by increasing antioxidant capacity and inhibiting cell apoptosis. In this study, we investigated the putative involvement of lncRNA AK046177 and microRNA-134 (miR-134) regulation in SYB against ischemia/reperfusion- (I/R-) induced neuronal injury. I/R and oxygen-glucose deprivation/reoxygenation (OGD/R) were established and . Cerebral infarct volume, neuronal apoptosis, and protein expression were detected. The effects of SYB on cell activity, cell respiration, nuclear factor erythroid 2-related factor 2 (Nrf2), antioxidant enzymes, and ROS were evaluated. I/R or OGD/R upregulated the expression of AK046177 and miR-134 and subsequently inhibited the activation and expression of CREB, which caused ROS generation and brain/cell injury. SYB attenuated the effects of AK046177, inhibited miR-134 expression, and promoted CREB activation, which in turn promoted Nrf2 expression, and then increased antioxidant capacities, improved cell respiration, and reduced apoptosis. We suggested that the antioxidant effects of SYB were driven by an AK046177/miR-134/CREB-dependent mechanism that inhibited this pathway, and that SYB has potential use in reducing or possibly preventing I/R-induced neuronal injury. 10.1155/2020/4586839
    Melatonin Alleviates Intracerebral Hemorrhage-Induced Secondary Brain Injury in Rats via Suppressing Apoptosis, Inflammation, Oxidative Stress, DNA Damage, and Mitochondria Injury. Wang Zhong,Zhou Feng,Dou Yang,Tian Xiaodi,Liu Chenglin,Li Haiying,Shen Haitao,Chen Gang Translational stroke research Intracerebral hemorrhage (ICH) is a cerebrovascular disease with high mortality and morbidity, and the effective treatment is still lacking. We designed this study to investigate the therapeutic effects and mechanisms of melatonin on the secondary brain injury (SBI) after ICH. An in vivo ICH model was induced via autologous whole blood injection into the right basal ganglia in Sprague-Dawley (SD) rats. Primary rat cortical neurons were treated with oxygen hemoglobin (OxyHb) as an in vitro ICH model. The results of the in vivo study showed that melatonin alleviated severe brain edema and behavior disorders induced by ICH. Indicators of blood-brain barrier (BBB) integrity, DNA damage, inflammation, oxidative stress, apoptosis, and mitochondria damage showed a significant increase after ICH, while melatonin reduced their levels. Meanwhile, melatonin promoted further increasing of expression levels of antioxidant indicators induced by ICH. Microscopically, TUNEL and Nissl staining showed that melatonin reduced the numbers of ICH-induced apoptotic cells. Inflammation and DNA damage indicators exhibited an identical pattern compared to those above. Additionally, the in vitro study demonstrated that melatonin reduced the apoptotic neurons induced by OxyHb and protected the mitochondrial membrane potential. Collectively, our investigation showed that melatonin ameliorated ICH-induced SBI by impacting apoptosis, inflammation, oxidative stress, DNA damage, brain edema, and BBB damage and reducing mitochondrial membrane permeability transition pore opening, and melatonin may be a potential therapeutic agent of ICH. 10.1007/s12975-017-0559-x
    Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of pyroptosis and neuroinflammation. Chen Junhui,Zhang Chunlei,Yan Tengfeng,Yang Lixiang,Wang Yuhai,Shi Zhonghua,Li Mingchang,Chen Qianxue Journal of cellular physiology Subarachnoid hemorrhage (SAH) is a subtype of stroke with high mortality and morbidity due to the lack of effective therapy. Atorvastatin has been reported to alleviate early brain injury (EBI) following subarachnoid hemorrhage (SAH) via reducing reactive oxygen species, antiapoptosis, regulated autophagy, and neuroinflammation. Which was the related to the pyroptosis? Pyroptosis can be defined as a highly specific inflammatory programmed cell death, distinct from classical apoptosis and necrosis. However, the precise role of pyroptosis in atorvastatin-mediated neuroprotection following SAH has not been confirmed. The present study aimed to investigate the neuroprotection and potential molecular mechanisms of atorvastatin in the SAH-induced EBI via regulating neural pyroptosis using the filament perforation model of SAH in male C57BL/6 mice, and the hemin-induced neuron damage model in HT-22. Atorvastatin or vehicle was administrated 2 h after SAH and hemin-induced neuron damage. The mortality, neurological score, brain water content, and neuronal death were evaluated. The results show that the atorvastatin treatment markedly increased survival rate, neurological score, greater survival of neurons, downregulated the protein expression of NLRP1, cleaved caspase-1, interleukin-1β (IL-1β), and IL-18, which indicated that atorvastatin-inhibited pyroptosis and neuroinflammation, ameliorated neuron death in vivo/vitro subjected to SAH. Taken together, this study demonstrates that atorvastatin improved the neurological outcome in rats and reduced the neuron death by against neural pyroptosis and neuroinflammation. 10.1002/jcp.30351
    Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia. Johann Sonja,Beyer Cordian The Journal of steroid biochemistry and molecular biology The neuroactive steroids 17β-estradiol and progesterone control a broad spectrum of neural functions. Besides their roles in the regulation of classical neuroendocrine loops, they strongly influence motor and cognitive systems, behavior, and modulate brain performance at almost every level. Such a statement is underpinned by the widespread and lifelong expression pattern of all types of classical and non-classical estrogen and progesterone receptors in the CNS. The life-sustaining power of neurosteroids for tattered or seriously damaged neurons aroused interest in the scientific community in the past years to study their ability for therapeutic use under neuropathological challenges. Documented by excellent studies either performed in vitro or in adequate animal models mimicking acute toxic or chronic neurodegenerative brain disorders, both hormones revealed a high potency to protect neurons from damage and saved neural systems from collapse. Unfortunately, neurons, astroglia, microglia, and oligodendrocytes are comparably target cells for both steroid hormones. This hampers the precise assignment and understanding of neuroprotective cellular mechanisms activated by both steroids. In this article, we strive for a better comprehension of the mutual reaction between these steroid hormones and the two major glial cell types involved in the maintenance of brain homeostasis, astroglia and microglia, during acute traumatic brain injuries such as stroke and hypoxia. In particular, we attempt to summarize steroid-activated cellular signaling pathways and molecular responses in these cells and their contribution to dampening neuroinflammation and neural destruction. This article is part of a Special Issue entitled 'CSR 2013'. 10.1016/j.jsbmb.2012.11.006
    Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia-Ischemia in the Immature Rat Brain. Sanches Eduardo,van de Looij Yohan,Sow Sadou,Toulotte Audrey,da Silva Analina,Modernell Laura,Sizonenko Stéphane Nutrients Injuries to the developing brain due to hypoxia-ischemia (HI) are common causes of neurological disabilities in preterm babies. HI, with oxygen deprivation to the brain or reduced cerebral blood perfusion due to birth asphyxia, often leads to severe brain damage and sequelae. Injury mechanisms include glutamate excitotoxicity, oxidative stress, blood-brain barrier dysfunction, and exacerbated inflammation. Nutritional intervention is emerging as a therapeutic alternative to prevent and rescue brain from HI injury. Lactoferrin (Lf) is an iron-binding protein present in saliva, tears, and breast milk, which has been shown to have antioxidant, anti-inflammatory and anti-apoptotic properties when administered to mothers as a dietary supplement during pregnancy and/or lactation in preclinical studies of developmental brain injuries. However, despite Lf's promising neuroprotective effects, there is no established dose. Here, we tested three different doses of dietary maternal Lf supplementation using the postnatal day 3 HI model and evaluated the acute neurochemical damage profile using H Magnetic Resonance Spectroscopy (MRS) and long-term microstructure alterations using advanced diffusion imaging (DTI/NODDI) allied to protein expression and histological analysis. Pregnant Wistar rats were fed either control diet or bovine Lf supplemented chow at 0.1, 1, or 10 g/kg/body weight concentration from the last day of pregnancy (embryonic day 21-E21) to weaning. At postnatal day 3 (P3), pups from both sexes had their right common carotid artery permanently occluded and were exposed to 6% oxygen for 30 min. Sham rats had the incision but neither surgery nor hypoxia episode. At P4, MRS was performed on a 9.4 T scanner to obtain the neurochemical profile in the cortex. At P4 and P25, histological analysis and protein expression were assessed in the cortex and hippocampus. Brain volumes and ex vivo microstructural analysis using DTI/NODDI parameters were performed at P25. Acute metabolic disturbance induced in cortical tissue by HIP3 was reversed with all three doses of Lf. However, data obtained from MRS show that Lf neuroprotective effects were modulated by the dose. Through western blotting analysis, we observed that HI pups supplemented with Lf at 0.1 and 1 g/kg were able to counteract glutamatergic excitotoxicity and prevent metabolic failure. When 10 g/kg was administered, we observed reduced brain volumes, increased astrogliosis, and hypomyelination, pointing to detrimental effects of high Lf dose. In conclusion, Lf supplementation attenuates, in a dose-dependent manner, the acute and long-term cerebral injury caused by HI. Lf reached its optimal effects at a dose of 1 g/kg, which pinpoints the need to better understand effects of Lf, the pathways involved and possible harmful effects. These new data reinforce our knowledge regarding neuroprotection in developmental brain injury using Lf through lactation and provide new insights into lactoferrin's neuroprotection capacities and limitation for immature brains. 10.3390/nu13113880
    Oxidative Stress Biomarkers of Brain Damage: Hyperacute Plasma F2-Isoprostane Predicts Infarct Growth in Stroke. Lorenzano Svetlana,Rost Natalia S,Khan Muhib,Li Hua,Lima Fabricio O,Maas Matthew B,Green Rebecca E,Thankachan Tijy K,Dipietro Allison J,Arai Ken,Som Angel T,Pham Loc-Duyen D,Wu Ona,Harris Gordon J,Lo Eng H,Blumberg Jeffrey B,Milbury Paul E,Feske Steven K,Furie Karen L Stroke BACKGROUND AND PURPOSE:Oxidative stress is an early response to cerebral ischemia and is likely to play an important role in the pathogenesis of cerebral ischemic injury. We sought to evaluate whether hyperacute plasma concentrations of biomarkers of oxidative stress, inflammation, and tissue damage predict infarct growth (IG). METHODS:We prospectively measured plasma F2-isoprostane (F2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguoanosine, plasma oxygen radical absorbance capacity assay, high sensitivity C reactive protein, and matrix metalloproteinase 2 and 9 in consecutive patients with acute ischemic stroke presenting within 9 hours of symptom onset. Patients with baseline diffusion-weighted magnetic resonance imaging and follow-up diffusion-weighted imaging or computed tomographic scan were included to evaluate the final infarct volume. Baseline diffusion-weighted imaging volume and final infarct volume were analyzed using semiautomated volumetric method. IG volume was defined as the difference between final infarct volume and baseline diffusion-weighted imaging volume. RESULTS:A total of 220 acute ischemic stroke subjects were included in the final analysis. One hundred seventy of these had IG. Baseline F2-isoP significantly correlated with IG volume (Spearman ρ=0.20; =0.005) and final infarct volume (Spearman ρ=0.19; =0.009). In a multivariate binary logistic regression model, baseline F2-isoP emerged as an independent predictor of the occurrence of IG (odds ratio, 2.57; 95% confidence interval, 1.37-4.83; =0.007). In a multivariate linear regression model, baseline F2-isoP was independently associated with IG volume (B, 0.38; 95% confidence interval, 0.04-0.72; =0.03). CONCLUSIONS:Elevated hyperacute plasma F2-isoP concentrations independently predict the occurrence of IG and IG volume in patients with acute ischemic stroke. If validated in future studies, measuring plasma F2-isoP might be helpful in the acute setting to stratify patients with acute ischemic stroke for relative severity of ischemic injury and expected progression. 10.1161/STROKEAHA.117.018440
    Genetic Screen for Cell Fitness in High or Low Oxygen Highlights Mitochondrial and Lipid Metabolism. Jain Isha H,Calvo Sarah E,Markhard Andrew L,Skinner Owen S,To Tsz-Leung,Ast Tslil,Mootha Vamsi K Cell Human cells are able to sense and adapt to variations in oxygen levels. Historically, much research in this field has focused on hypoxia-inducible factor (HIF) signaling and reactive oxygen species (ROS). Here, we perform genome-wide CRISPR growth screens at 21%, 5%, and 1% oxygen to systematically identify gene knockouts with relative fitness defects in high oxygen (213 genes) or low oxygen (109 genes), most without known connection to HIF or ROS. Knockouts of many mitochondrial pathways thought to be essential, including complex I and enzymes in Fe-S biosynthesis, grow relatively well at low oxygen and thus are buffered by hypoxia. In contrast, in certain cell types, knockout of lipid biosynthetic and peroxisomal genes causes fitness defects only in low oxygen. Our resource nominates genetic diseases whose severity may be modulated by oxygen and links hundreds of genes to oxygen homeostasis. 10.1016/j.cell.2020.03.029
    High-flow nasal cannula therapy for initial oxygen administration in acute hypercapnic respiratory failure: study protocol of randomised controlled unblinded trial. Alnajada Asem,Blackwood Bronagh,Mobrad Abdulmajeed,Akhtar Adeel,Shyamsundar Murali BMJ open respiratory research INTRODUCTION:Acute respiratory failure is a common clinical condition accounting for nearly 116 000 admissions in the UK hospitals. Acute type 2 respiratory failure is also called acute hypercapnic respiratory failure (AHRF) and characterised by an elevated arterial CO level of >6 kPa due to pump failure. Acute exacerbation of chronic obstructive pulmonary disease is the most common cause of AHRF. High-flow nasal therapy (HFNT) is a new oxygen delivery system that uses an oxygen-air blender to deliver flow rates of up to 60 L/min. The gas is delivered humidified and heated to the patient via wide-bore nasal cannula. METHODS AND ANALYSIS:We hypothesised that HFNC as the initial oxygen administration method will reduce the number of patients with AHRF requiring non-invasive ventilation in patients at 6 hours post intervention when compared with low-flow nasal oxygen (LFO). A randomised single-centre unblinded controlled trial is designed to test our hypothesis. The trial will compare two oxygen administration methods, HFNT versus LFO. Patients will be randomised to one of the two arms if they fulfil the eligibility criteria. The sample size is 82 adult patients (41 HFNT and 41 LFO) presenting to the emergency department. ETHICS AND DISSEMINATION:Ethical approval was obtained from the Office for Research Ethics Committees Northern Ireland (REC reference: 20/NI/0049). Dissemination will be achieved in several ways: (1) the findings will be presented at national and international meetings with open-access abstracts online and (2) in accordance with the open-access policies proposed by the leading research funding bodies we aim to publish the findings in high-quality peer-reviewed open-access journals. TRIAL REGISTRATION NUMBER:The trial was prospectively registered at the clinicaltrials.gov registry (NCT04640948) on 20 November 2020. 10.1136/bmjresp-2020-000853
    Enhanced epithelial sodium channel activity in neonatal Scnn1b mouse lung attenuates high oxygen-induced lung injury. American journal of physiology. Lung cellular and molecular physiology Prolonged oxygen therapy leads to oxidative stress, epithelial dysfunction, and acute lung injury in preterm infants and adults. Heterozygous Scnn1b mice, which overexpress lung epithelial sodium channels (ENaC), and their wild-type (WT) C57Bl6 littermates were utilized to study the pathogenesis of high fraction inspired oxygen ([Formula: see text])-induced lung injury. Exposure to high [Formula: see text] from birth to () was used to model oxidative stress. Chronic exposure of newborn pups to 85% O increased glutathione disulfide (GSSG) and elevated the GSH/GSSG redox potential () of bronchoalveolar lavage fluid (BALF). Longitudinal X-ray imaging and Evans blue-labeled-albumin assays showed that chronic 85% O and acute GSSG (400 µM) exposures decreased alveolar fluid clearance (AFC) in the WT lung. Morphometric analysis of WT pups insufflated with GSSG (400 µM) or amiloride (1 µM) showed a reduction in alveologenesis and increased lung injury compared with age-matched control pups. The Scnn1b mouse lung phenotype was not further aggravated by chronic 85% O exposure. These outcomes support the hypothesis that exposure to hyperoxia increases GSSG, resulting in reduced lung fluid reabsorption due to inhibition of amiloride-sensitive ENaC. Flavin adenine dinucleotide (FADH; 10 µM) was effective in recycling GSSG in vivo and promoted alveologenesis, but did not impact AFC nor attenuate fibrosis following high [Formula: see text] exposure. In conclusion, the data indicate that FADH may be pivotal for normal lung development, and show that ENaC is a key factor in promoting alveologenesis, sustaining AFC, and attenuating fibrotic lung injury caused by prolonged oxygen therapy in WT mice. 10.1152/ajplung.00538.2020
    High flow nasal oxygen for acute type two respiratory failure: a systematic review. Alnajada Asem Abdulaziz,Blackwood Bronagh,Mobrad Abdulmajeed,Akhtar Adeel,Pavlov Ivan,Shyamsundar Murali F1000Research Acute type two respiratory failure (AT2RF) is characterized by high carbon dioxide levels (PaCO >6kPa). Non-invasive ventilation (NIV), the current standard of care, has a high failure rate. High flow nasal therapy (HFNT) has potential additional benefits such as CO clearance, the ability to communicate and comfort. The primary aim of this systematic review is to determine whether HFNT in AT2RF improves 1) PaCO , 2) clinical and patient-centred outcomes and 3) to assess potential harms. We searched EMBASE, MEDLINE and CENTRAL  (January 1999-January 2021). Randomised controlled trials (RCTs) and cohort studies comparing HFNT with low flow nasal oxygen (LFO) or NIV were included. Two authors independently assessed studies for eligibility, data extraction and risk of bias. We used Cochrane risk of bias tool for RCTs and Ottawa-Newcastle scale for cohort studies. From 727 publications reviewed, four RCTs and one cohort study (n=425) were included. In three trials of HFNT vs NIV, comparing PaCO (kPa) at last follow-up time point, there was a significant reduction at four hours (1 RCT; HFNT median 6.7, IQR 5.6 - 7.7 vs NIV median 7.6, IQR 6.3 - 9.3) and no significant difference at  24-hours or five days. Comparing HFNT with LFO, there was no significant difference at 30-minutes. There was no difference in intubation or mortality. This review identified a small number of studies with low to very low certainty of evidence. A reduction of PaCO at an early time point of four hours post-intervention was demonstrated in one small RCT. Significant limitations of the included studies were lack of adequately powered outcomes and clinically relevant time-points and small sample size. Accordingly, systematic review cannot recommend the use of HFNT as the initial management strategy for AT2RF and trials adequately powered to detect clinical and patient-relevant outcomes are urgently warranted. 10.12688/f1000research.52885.2
    [Efficacy of high flow nasal oxygen therapy in children with acute respiratory failure]. Lu Y,Cui Y,Shi J Y,Zhou Y P,Wang C X,Zhang Y C Zhonghua er ke za zhi = Chinese journal of pediatrics To investigate the efficacy of high flow nasal cannula (HFNC) in children with acute respiratory failure. A prospective study was conducted. A total of 153 patients aged from 1 to 14 years with acute respiratory failure were enrolled, who were admitted to pediatric intensive care unit (PICU) of Shanghai Children's Hospital from January 2018 to December 2019. HFNC success was defined as no need for invasive mechanical ventilation and successfully withdrawn from HFNC, while HFNC failure was defined as need for invasive mechanical ventilation. HFNC at a flow rate of 2 L/(kg·min) (maximum ≤ 60 L/min) with inhaled oxygen concentration (FiO) between 0.30 and 1.00 was applied to maintain percutaneous oxygen saturation (SpO) of 0.94-0.97. Parameters including arterial partial pressure of oxygen (PaO), partial pressure of carbon dioxide in artery (PaCO), SpO and PaO/FiO were collected before and during the application of HFNC at 1 h, 6 h, 12 h, 24 h and 48 h, as well as over 48 h after HFNC withdrawn. Comparison between the groups was performed by student test, Mann-Whitney test or chi-square test. The sensitivity and specificity of the above parameters in predicting HFNC success were evaluated by receiver operating characteristic (ROC) curve. A total of 153 children (70 males and 83 females) were enrolled. Among them, 131 (85.6%) cases were successfully weaned off from HFNC and 22 (14.4%) failed. The duration of HFNC was 57 (38, 95) hours in the successful group, and the PaO/FiO before HFNC application and after HFNC was withdrawn were 187 (170, 212) mmHg (1 mmHg=0.133 kPa) and 280 (262, 292) mmHg, respectively. The duration of HFNC in the failure group was 19 (9, 49) hours, and the PaO/FiO before HFNC application and after HFNC withdrawn were 176 (171, 189) mmHg and 159 (156, 161) mmHg, respectively. The values of PaO/FiO were significantly higher in the successful group than those in the failed group at using HFNC initially 1 h (196 (182, 211) 174 (160, 178) mmHg, =-5.105, 0.01), 6 h (213 (203, 220) 168 (157, 170) mmHg, =-6.772, 0.01), 12 h (226 (180, 261) 165 (161, 170) mmHg, =-4.308, 0.01), 24 h (229 (195, 259) 165 (161, 170) mmHg, =-4.609, 0.01) and 48 h (249 (216, 273) 163 (158, 169) mmHg, =-4.628, 0.01) after the HFNC application, and over 48 h after HFNC was withdrawn (277 (268, 283) 157 (154, 158) mmHg, =-3.512, 0.01). Moreover, the PaO levels were significantly higher in the successful group than those in the failed group using HFNC initially at 1 h (73.7 (71.0, 76.7) 70.0 (66.2, 71.2) mmHg, =-4.587, 0.01) and 6 h (79.0 (75.0, 82.0) 71.0 (62.0, 72.0) mmHg, =-5.954, 0.01) after HFNC application. Also, the SpO levels showed the same differences at 1 h (0.96 (0.95, 0.96) 0.94 (0.92, 0.94), =-4.812, 0.01) and 6 h (0.96 (0.95, 0.97) 0.94(0.91, 0.95), =-5.024, 0.01) after HFNC application. Forty eight hours after HFNC was withdrawn, the PaO (88.0 (81.7, 95.0) 63.7 (63.3, 66.0) mmHg, =-3.032, 0.01) and SpO (0.96 (0.94, 0.98) 0.91 (0.90, 0.92), =-3.957, 0.01) were also significantly higher in the successful group. Regarding the HFNC complications, there was one case with atelectasis and one with pneumothorax in the failure group. HFNC was used as sequential oxygen therapy after extubation in 79 children, successful in all. ROC curve showed that the area under curve of PaO/FiO in predicting HFNC success was 0.990, and the optimal cut-off value was 232 mmHg with the 95 of 0.970-1.000 (0.01). HFNC could be used as a respiratory support strategy for children with mild to moderate respiratory failure and as a sequential oxygen therapy after extubation. The PaO/FiO when HFNC withdrow is the optimal index to evaluate the success of HFNC application. 10.3760/cma.j.cn112140-20200612-00617
    Limitations of the ARDS criteria during high-flow oxygen or non-invasive ventilation: evidence from critically ill COVID-19 patients. Hultström Michael,Hellkvist Ola,Covaciu Lucian,Fredén Filip,Frithiof Robert,Lipcsey Miklós,Perchiazzi Gaetano,Pellegrini Mariangela Critical care (London, England) BACKGROUND:The ratio of partial pressure of arterial oxygen to inspired oxygen fraction (PaO/FO) during invasive mechanical ventilation (MV) is used as criteria to grade the severity of respiratory failure in acute respiratory distress syndrome (ARDS). During the SARS-CoV2 pandemic, the use of PaO/FO ratio has been increasingly used in non-invasive respiratory support such as high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV). The grading of hypoxemia in non-invasively ventilated patients is uncertain. The main hypothesis, investigated in this study, was that the PaO/FO ratio does not change when switching between MV, NIV and HFNC. METHODS:We investigated respiratory function in critically ill patients with COVID-19 included in a single-center prospective observational study of patients admitted to the intensive care unit (ICU) at Uppsala University Hospital in Sweden. In a steady state condition, the PaO/FO ratio was recorded before and after any change between two of the studied respiratory support techniques (i.e., HFNC, NIV and MV). RESULTS:A total of 148 patients were included in the present analysis. We find that any change in respiratory support from or to HFNC caused a significant change in PaO/FO ratio. Changes in respiratory support between NIV and MV did not show consistent change in PaO/FO ratio. In patients classified as mild to moderate ARDS during MV, the change from HFNC to MV showed a variable increase in PaO/FO ratio ranging between 52 and 140 mmHg (median of 127 mmHg). This made prediction of ARDS severity during MV from the apparent ARDS grade during HFNC impossible. CONCLUSIONS:HFNC is associated with lower PaO/FO ratio than either NIV or MV in the same patient, while NIV and MV provided similar PaO/FO and thus ARDS grade by Berlin definition. The large variation of PaO/FO ratio indicates that great caution should be used when estimating ARDS grade as a measure of pulmonary damage during HFNC. 10.1186/s13054-022-03933-1
    Velocity-based target flow rate for high-flow nasal cannula oxygen therapy. Kusubae Ryo,Hirabayashi Masako,Nakazaki Naho,Shinkoda Yuichi Pediatrics international : official journal of the Japan Pediatric Society BACKGROUND:The aim of this study was to assess retrospectively whether the average inspiratory flow velocity-based initial flow rate in high-flow nasal cannula (HFNC) therapy could be well tolerated and safely used for infants and children hospitalized with moderate to severe respiratory failure. METHODS:Thirty-three patients without underlying diseases (22 males; 67%), hospitalized to receive HFNC therapy for infection-related respiratory failure, were analyzed. The median age was 2 months (interquartile range, 1 month to 1 year). Patients with dyspnea and carbon dioxide partial pressure (pCO ) >50 mmHg or venous blood pH <7.320, combined with pulse oximetry arterial oxygen saturation <92%, were included. We set target flow rates calculated from the average inspiratory flow velocity, starting at the actual initial flow rates, and these were subsequently adjusted if necessary. RESULTS:One patient could not tolerate the cannula. Of the remaining 32 patients, 81% (n = 26) had an actual initial flow rate within 1 L of the target flow rate; these patients were evaluated for changes in the fraction of inspired oxygen (FITarget flow rate tableO ), pH, and pCO values after 24 h. Three patients required a higher fraction of inspired oxygen, one showed a persistent pH < 7.320, and seven exhibited pCO >50 mmHg. No patient required non-invasive positive-pressure ventilation, and one required intubation. Pneumothorax was not reported in any patient. CONCLUSIONS:The average inspiratory flow velocity-based initial flow rate was well-tolerated without sedation, and there were no severe complications. Starting at this flow rate would improve the use of HFNC therapy in the pediatric ward, possibly reducing the need for more invasive modes of ventilation. 10.1111/ped.14545
    Randomised cross-over study of automated oxygen control for preterm infants receiving nasal high flow. Reynolds Peter R,Miller Thomas L,Volakis Leonithas I,Holland Nicky,Dungan George C,Roehr Charles Christoph,Ives Kevin Archives of disease in childhood. Fetal and neonatal edition OBJECTIVE:To evaluate a prototype automated controller (IntellO) of the inspired fraction of oxygen (FiO) in maintaining a target range of oxygen saturation (SpO) in preterm babies receiving nasal high flow (HF) via the Vapotherm Precision Flow. DESIGN:Prospective two-centre order-randomised cross-over study. SETTING:Neonatal intensive care units. PATIENTS:Preterm infants receiving HF with FiO ≥25%. INTERVENTION:Automated versus manual control of FiO to maintain a target SpO range of 90%-95% (or 90%-100% if FiO=21%). MAIN OUTCOME MEASURES:The primary outcome measure was per cent of time spent within target SpO range. Secondary outcomes included the overall proportion and durations of SpO within specified hyperoxic and hypoxic ranges and the number of in-range episodes per hour. RESULTS:Data were analysed from 30 preterm infants with median (IQR) gestation at birth of 26 (24-27) weeks, study age of 29 (18-53) days and study weight 1080 (959-1443) g. The target SpO range was achieved 80% of the time on automated (IntellO) control (IQR 70%-87%) compared with 49% under manual control (IQR 40%-57%; p<0.0001). There were fewer episodes of SpO below 80% lasting at least 60 s under automated control (0 (IQR 0-1.25)) compared with manual control (5 (IQR 2.75-14)). There were no differences in the number of episodes per hour of SpO above 98% (4.5 (IQR 1.8-8.5) vs 5.5 (IQR 1.9-14); p=0.572) between the study arms. CONCLUSIONS:The IntellO automated oxygen controller maintained patients in the target SpO range significantly better than manual adjustments in preterm babies receiving HF. TRIAL REGISTRATION NUMBER:NCT02074774. 10.1136/archdischild-2018-315342
    High-Flow Nasal Cannula Oxygen Therapy versus Non-Invasive Ventilation for AECOPD Patients After Extubation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. International journal of chronic obstructive pulmonary disease Objective:To evaluate the clinical efficacy of high-flow nasal oxygen therapy (HFNC) and non-invasive ventilation (NIV) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) after extubation. Research Methods:This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statements. The primary outcome measures analyzed included: reintubation rate, mortality, complication rate, and ICU length of stay. Results:Eight studies were included, with a total of 612 subjects, including 297 in the HFNC group and 315 in the NIV group. The effect of HFNC and NIV on the reintubation rate of AECOPD patients after extubation, RR (1.49 [95% CI,0.95 to 2.33], P = 0.082). Subgroup analysis with or without hypercapnia according to the included AECOPD population, with hypercapnia, RR (0.69 [95% CI,0.33 to 1.44], P=0.317), without hypercapnia, RR (2.61 [95% CI,1.41 to 4.83], P=0.002). Mortality, RR (0.92 [95% CI,0.56 to 1.52], P = 0.752). ICU length of stay, MD (-0.44 [95% CI,-1.01 to 0.13], P = 0.132). Complication rate, RR (0.22 [95% CI,0.13 to 0.39], P = 0.000). After subgroup analysis, the reintubation rate of HFNC and NIV has no statistical difference in patients with hypercapnia, but NIV can significantly reduce the reintubation rate in patients without hypercapnia. In the outcome measures of complication rate, HFNC significantly reduced complication rate compared with NIV. In mortality and ICU length of stay, analysis results showed that HFNC and NIV were not statistically different. Conclusion:According to the available evidence, the application of HFNC can be used as an alternative treatment for NIV after extubation in AECOPD patients with hypercapnia, but in the patients without hypercapnia, HFNC is less effective than NIV. 10.2147/COPD.S375107
    Comparison of high-flow and conventional nasal cannula oxygen in patients undergoing endobronchial ultrasonography. Yilmazel Ucar Elif,Araz Ömer,Kerget Bugra,Akgun Metin,Saglam Leyla Internal medicine journal BACKGROUND:Oxygen therapy is required to prevent hypoxaemia during the endobronchial ultrasonography (EBUS) procedure. AIMS:To compare the effectiveness of oxygen therapy delivered through high-flow nasal cannula (HFNC) and conventional nasal cannula (CNC) in patients undergoing EBUS. The primary outcome was the proportion of patients who desaturated. Patient compliance and satisfaction were also evaluated. METHODS:This single-centre prospective interventional study was conducted in a tertiary hospital among patients who presented to the EBUS unit in 2018 and 2019. Patients were randomly assigned to the HFNC group or the CNC group. RESULTS:The study included 170 patients (111 men and 59 women) with a mean age of 58 ± 14 years. The number of patients experiencing desaturation while receiving oxygen was statistically significantly lower (P < 0.001) in the HFNC group (n = 5) compared with the CNC group (n = 26). Oxygen therapy was adjusted in two patients in the CNC group due to desaturation. Saturation was significantly higher in the HFNC group (P < 0.0001) at the end of the EBUS procedure. Heart rate at the end of EBUS was lower in the HFNC group, but this difference was not statistically significant (96 ± 16 vs 101 ± 19, P = 0.13). Five patients in the HFNC group and 18 patients in the CNC group reported discomfort during the procedure (P = 0.006). CONCLUSION:Oxygen therapy delivered by HFNC seems to be safer and more effective than by CNC in patients undergoing EBUS. Oxygen therapy with HFNC may be considered as an alternative to CNC because it may increase patient comfort and thereby improve compliance. 10.1111/imj.15001
    Initial setting of high-flow nasal oxygen post extubation based on mean inspiratory flow during a spontaneous breathing trial. Butt Sophia,Pistidda Laura,Floris Leda,Liperi Corrado,Vasques Francesco,Glover Guy,Barrett Nicholas A,Sanderson Barnaby,Grasso Salvatore,Shankar-Hari Manu,Camporotaa Luigi Journal of critical care PURPOSE:High flow nasal cannula (HFNC) is commonly used post-extubation in intensive care (ICU). Patients' comfort during HFNC is affected by flow rate. The study aims to describe the relationship between pre-extubation inspiratory flow requirements and the post-extubation flow rates on HFNC that maximises patient's comfort. METHODS:This was an observational, retrospective study conducted in a university-affiliated ICU. We included patients extubated following successful spontaneous breathing trial (SBT). During the SBT we recorded variables including inspiratory flow. Patients who passed the SBT were extubated onto HFNC. HFNC was titrated from 20 L/min and increased in steps of 10 L/min, up to 60 L/min. At each step, patient's level of comfort was assessed. Fraction of inspired oxygen was titrated to maintain oxygen saturation 92-97%. RESULTS:Nineteen participants were enrolled in the study. There was a significant positive correlation between mean inspiratory flow pre-extubation and the flow setting on HFNC which achieved the best comfort post-extubation (r 0.88; p < 0.001). Overall, greatest comfort was observed for HFNC flows between 30 and 40 L/min but with individual variability. CONCLUSION:Measuring mean inspiratory flow during an SBT allows for individualised setting of HFNC flow rate immediately post-extubation and achieves the greatest comfort and interface tolerance. 10.1016/j.jcrc.2020.12.022
    Pulse oximetric saturation to fraction of inspired oxygen (SpO/FIO) ratio 24 hours after high-flow nasal cannula (HFNC) initiation is a good predictor of HFNC therapy in patients with acute exacerbation of interstitial lung disease. Koyauchi Takafumi,Yasui Hideki,Enomoto Noriyuki,Hasegawa Hirotsugu,Hozumi Hironao,Suzuki Yuzo,Karayama Masato,Furuhashi Kazuki,Fujisawa Tomoyuki,Nakamura Yutaro,Inui Naoki,Yokomura Koshi,Suda Takafumi Therapeutic advances in respiratory disease BACKGROUND:High-flow nasal cannula (HFNC) oxygen therapy provides effective respiratory management in patients with hypoxemic respiratory failure. However, the efficacy and tolerability of HFNC for patients with acute exacerbation of interstitial lung disease (AE-ILD) have not been established. This study was performed to assess the efficacy and tolerability of HFNC for patients with AE-ILD and identify the early predictors of the outcome of HFNC treatment. METHODS:We retrospectively reviewed the records of patients with AE-ILD who underwent HFNC. Overall survival, the success rate of HFNC treatment, adverse events, temporary interruption of treatment, discontinuation of treatment at the patient's request, and predictors of the outcome of HFNC treatment were evaluated. RESULTS:A total of 66 patients were analyzed. Of these, 26 patients (39.4%) showed improved oxygenation and were successfully withdrawn from HFNC. The 30-day survival rate was 48.5%. No discontinuations at the patient's request were observed, and no serious adverse events occurred. The pulse oximetric saturation to fraction of inspired oxygen (SpO/FIO) ratio 24 h after initiating HFNC showed high prediction accuracy (area under the receiver operating characteristic curve, 0.802) for successful HFNC treatment. In the multivariate logistic regression analysis, an SpO/FIO ratio of at least 170.9 at 24 h after initiation was significantly associated with successful HFNC treatment (odds ratio, 51.3; 95% confidence interval, 6.13-430;  < 0.001). CONCLUSIONS:HFNC was well tolerated in patients with AE-ILD, suggesting that HFNC is a reasonable respiratory management for these patients. The SpO/FIO ratio 24 h after initiating HFNC was a good predictor of successful HFNC treatment. 10.1177/1753466620906327
    Perioperative high inspired oxygen fraction induces atelectasis in patients undergoing abdominal surgery: A randomized controlled trial. Park MiHye,Jung Kangha,Sim Woo Seog,Kim Duk Kyung,Chung In Sun,Choi Ji Won,Lee Eun Jee,Lee Nam Young,Kim Jie Ae Journal of clinical anesthesia STUDY OBJECTIVE:We evaluated the feasibility of use and effects on postoperative atelectasis and complications of lower inspired oxygen fraction (FIO) compared to conventional oxygen therapy. DESIGN:Single center, randomized clinical trial. SETTING:University hospital, operating room and postoperative recovery area. PATIENTS:One hundred ninety patients aged ≥50 with an American Society of Anesthesiologists physical status of I-III who underwent abdominal surgery with general anesthesia. INTERVENTIONS:Participants were randomly assigned to either the low FIO group (intraoperative: FIO 0.35, during induction and recovery: FIO 0.7) or the conventional FIO group (intraoperative: FIO 0.6, during induction and recovery: FIO 1.0). MEASUREMENTS:The primary outcome was postoperative atelectasis measured with lung ultrasonography at postoperative 30 min in the post-anesthesia care unit (consolidation score: each region 0-3, 12 region, total score range of 0 to 36, a lower score indicating better aeration). MAIN RESULTS:Seven patients in the low FIO group were omitted from the study due to changing FIO during intervention (7/95 (8.4%) vs. 2/95 (2.1%), p = 0.088; low FIO group vs. conventional FIO group). Overall, atelectasis was detected in 29.7% (51/172) of patients 30 min after surgery by lung ultrasound and 40.1% (69/172) of patients after 2 days after surgery by chest X-ray. The scores of lung ultrasonography and the incidence of significant atelectasis (consolidation score ≥ 2 at any region) were lower in the low FIO group than in the conventional FIO group (median [IQR]: 3 [1,6] vs. 7 [3,9], p < 0.001 and 17/85 (20%) vs. 34/87 (39%), RR: 0.512 [95% CI: 0.311-0.843], p = 0.006, respectively). The incidence of surgical site infection and length of hospitalization were not significantly different between the two groups. CONCLUSIONS:Based on our findings, decreased inspired oxygen fraction during anesthesia and recovery did not cause hypoxic events, but instead reduced immediate postoperative atelectasis. The use of intraoperative conventional higher inspired oxygen did not afford any clinical advantages for postoperative recovery in abdominal surgery. 10.1016/j.jclinane.2021.110285
    Noninvasive ventilation and high-flow nasal oxygen for acute respiratory failure: is less more? Thille Arnaud W,Coudroy Rémi,Frat Jean-Pierre Current opinion in critical care PURPOSE OF REVIEW:High-flow nasal oxygen and noninvasive ventilation (NIV) are two strategies representing an alternative to standard oxygen in the management of respiratory failure. RECENT FINDINGS:Although high-flow nasal oxygen has shown promising results in patients with de-novo acute respiratory failure, further large clinical trials are needed to determine the best oxygenation strategy. As NIV may have deleterious effects, especially in patients generating strong inspiratory efforts, protective NIV using higher levels of positive-end expiratory pressure, more prolonged sessions and additional interfaces such as helmets should be assessed in the future. Whereas NIV is the first-line ventilation strategy in patients with acute exacerbation of chronic lung diseases, high-flow nasal oxygen could be an alternative to NIV after partial reversal of respiratory acidosis. To prevent severe hypoxemia during intubation of hypoxemic patients or to prevent postextubation respiratory failure in patients at high-risk of reintubation, NIV is the best strategy for preoxygenation or immediately after extubation in ICUs. SUMMARY:New large-scale clinical trials are needed to compare high-flow nasal oxygen with standard oxygen in patients with de-novo acute respiratory failure to determine the reference treatment. After which, more protective NIV could be assessed among the more severe patients. 10.1097/MCC.0000000000000785
    High-flow nasal oxygen as first-line therapy for COVID-19-associated hypoxemic respiratory failure: a single-centre historical cohort study. Canadian journal of anaesthesia = Journal canadien d'anesthesie PURPOSE:The optimal noninvasive modality for oxygenation support in COVID-19-associated hypoxemic respiratory failure and its association with healthcare worker infection remain uncertain. We report here our experience using high-flow nasal oxygen (HFNO) as the primary support mode for patients with COVID-19 in our institution. METHODS:We conducted a single-centre historical cohort study of all COVID-19 patients treated with HFNO for at least two hours in our university-affiliated and intensivist-staffed intensive care unit (Jewish General Hospital, Montreal, QC, Canada) between 27 August 2020 and 30 April 2021. We report their clinical characteristics and outcomes. Healthcare workers in our unit cared for these patients in single negative pressure rooms wearing KN95 or fit-tested N95 masks; they underwent mandatory symptomatic screening for COVID-19 infection, as well as a period of asymptomatic screening. RESULTS:One hundred and forty-two patients were analysed, with a median [interquartile range (IQR)] age of 66 [59-73] yr; 71% were male. Patients had a median [IQR] Sequential Organ Failure Assessment Score of 3 [2-3], median [IQR] oxygen saturation by pulse oximetry/fraction of inspired oxygen ratio of 120 [94-164], and a median [IQR] 4C score (a COVID-19-specific mortality score) of 12 [10-14]. Endotracheal intubation occurred in 48/142 (34%) patients, and overall hospital mortality was 16%. Barotrauma occurred in 21/142 (15%) patients. Among 27 symptomatic and 139 asymptomatic screening tests, there were no cases of HFNO-related COVID-19 transmission to healthcare workers. CONCLUSION:Our experience indicates that HFNO is an effective first-line therapy for hypoxemic respiratory failure in COVID-19 patients, and can be safely used without significant discernable infection risk to healthcare workers. 10.1007/s12630-022-02218-z
    Non-invasive ventilatory support and high-flow nasal oxygen as first-line treatment of acute hypoxemic respiratory failure and ARDS. Intensive care medicine The role of non-invasive respiratory support (high-flow nasal oxygen and noninvasive ventilation) in the management of acute hypoxemic respiratory failure and acute respiratory distress syndrome is debated. The oxygenation improvement coupled with lung and diaphragm protection produced by non-invasive support may help to avoid endotracheal intubation, which prevents the complications of sedation and invasive mechanical ventilation. However, spontaneous breathing in patients with lung injury carries the risk that vigorous inspiratory effort, combined or not with mechanical increases in inspiratory airway pressure, produces high transpulmonary pressure swings and local lung overstretch. This ultimately results in additional lung damage (patient self-inflicted lung injury), so that patients intubated after a trial of noninvasive support are burdened by increased mortality. Reducing inspiratory effort by high-flow nasal oxygen or delivery of sustained positive end-expiratory pressure through the helmet interface may reduce these risks. In this physiology-to-bedside review, we provide an updated overview about the role of noninvasive respiratory support strategies as early treatment of hypoxemic respiratory failure in the intensive care unit. Noninvasive strategies appear safe and effective in mild-to-moderate hypoxemia (PaO/FiO > 150 mmHg), while they can yield delayed intubation with increased mortality in a significant proportion of moderate-to-severe (PaO/FiO ≤ 150 mmHg) cases. High-flow nasal oxygen and helmet noninvasive ventilation represent the most promising techniques for first-line treatment of severe patients. However, no conclusive evidence allows to recommend a single approach over the others in case of moderate-to-severe hypoxemia. During any treatment, strict physiological monitoring remains of paramount importance to promptly detect the need for endotracheal intubation and not delay protective ventilation. 10.1007/s00134-021-06459-2
    Effects of high versus low inspiratory oxygen fraction on postoperative clinical outcomes in patients undergoing surgery under general anesthesia: A systematic review and meta-analysis of randomized controlled trials. Journal of clinical anesthesia OBJECTIVES:To determine whether high perioperative inspired oxygen fraction (FiO) compared with low FiO has more deleterious postoperative clinical outcomes in patients undergoing non-thoracic surgery under general anesthesia. DESIGN:Meta-analysis of randomized controlled trials. SETTING:Operating room, postoperative recovery room and surgical ward. PATIENTS:Surgical patients under general anesthesia. INTERVENTION:High perioperative FiO (≥0.8) vs. low FiO (≤0.5). MEASUREMENTS:The primary outcome was mortality within 30 days. Secondary outcomes were pulmonary outcomes (atelectasis, pneumonia, respiratory failure, postoperative pulmonary complications [PPCs], and postoperative oxygen parameters), intensive care unit (ICU) admissions, and length of hospital stay. A subgroup analysis was performed to explore the treatment effect by body mass index (BMI). MAIN RESULTS:Twenty-six trials with a total 4991 patients were studied. The mortality in the high FiO group did not differ from that in the low FiO group (risk ratio [RR] 0.91, 95% confidence interval [CI] 0.42-1.97, P = 0.810). Nor were there any significant differences between the groups in such outcomes as pneumonia (RR 1.19, 95% CI 0.74-1.92, P = 0.470), respiratory failure (RR 1.29, 95% CI 0.82-2.04, P = 0.270), PPCs (RR 1.05, 95% CI 0.69-1.59, P = 0.830), ICU admission (RR 0.94, 95% CI 0.55-1.60, P = 0.810), and length of hospital stay (mean difference [MD] 0.27 d, 95% CI -0.28-0.81, P = 0.340). The high FiO was associated with postoperative atelectasis more often (risk ratio 1.27, 95% CI 1.00-1.62, P = 0.050), and lower postoperative arterial partial oxygen pressure (MD -5.03 mmHg, 95% CI -7.90- -2.16, P < 0.001) In subgroup analysis of BMI >30 kg/m, these parameters were similarly affected between the groups. CONCLUSIONS:The use of high FiO compared to low FiO did not affect the short-term mortality, although it may increase the incidence of atelectasis in adult, non-thoracic patients undergoing surgical procedures. Nor were there any significant differences in other secondary outcomes. 10.1016/j.jclinane.2021.110461
    Moderate Certainty Evidence Suggests the Use of High-Flow Nasal Cannula Does Not Decrease Hypoxia When Compared With Conventional Oxygen Therapy in the Peri-Intubation Period: Results of a Systematic Review and Meta-Analysis. Chaudhuri Dipayan,Granton David,Wang Dominic Xiang,Einav Sharon,Helviz Yigal,Mauri Tommaso,Ricard Jean-Damien,Mancebo Jordi,Frat Jean-Pierre,Jog Sameer,Hernandez Gonzalo,Maggiore Salvatore M,Hodgson Carol,Jaber Samir,Brochard Laurent,Burns Karen E A,Rochwerg Bram Critical care medicine OBJECTIVE:The role of high-flow nasal cannula during and before intubation is unclear despite a number of randomized clinical trials. Our objective was to conduct a systematic review and meta-analysis examining the benefits of high-flow nasal cannula in the peri-intubation period. DATA SOURCES:We performed a comprehensive search of relevant databases (MEDLINE, EMBASE, and Web of Science). STUDY SELECTION:We included randomized clinical trials that compared high-flow nasal cannula to other noninvasive oxygen delivery systems in the peri-intubation period. DATA EXTRACTION:Our primary outcome was severe desaturation (defined as peripheral oxygen saturation reading < 80% during intubation). Secondary outcomes included peri-intubation complications, apneic time, PaO2 before and after intubation, PaCO2 after intubation, ICU length of stay, and short-term mortality. DATA SYNTHESIS:We included 10 randomized clinical trials (n = 1,017 patients). High-flow nasal cannula had no effect on the occurrence rate of peri-intubation hypoxemia (relative risk, 0.98; 95% CI, 0.68-1.42; 0.3% absolute risk reduction, moderate certainty), serious complications (relative risk, 0.87; 95% CI, 0.71-1.06), apneic time (mean difference, 10.3 s higher with high-flow nasal cannula; 95% CI, 11.0 s lower to 31.7 s higher), PaO2 measured after preoxygenation (mean difference, 3.6 mm Hg higher; 95% CI, 3.5 mm Hg lower to 10.7 mm Hg higher), or PaO2 measured after intubation (mean difference, 27.0 mm Hg higher; 95% CI, 13.2 mm Hg lower to 67.2 mm Hg higher), when compared with conventional oxygen therapy. There was also no effect on postintubation PaCO2, ICU length of stay, or 28-day mortality. CONCLUSIONS:We found moderate-to-low certainty evidence that the use of high-flow nasal cannula likely has no effect on severe desaturation, serious complications, apneic time, oxygenation, ICU length of stay, or overall survival when used in the peri-intubation period when compared with conventional oxygen therapy. 10.1097/CCM.0000000000004217
    Construction of pH-Dependent Nanozymes with Oxygen Vacancies as the High-Efficient Reactive Oxygen Species Scavenger for Oral-Administrated Anti-Inflammatory Therapy. Zhao Ning,Yang Fei-Er,Zhao Cong-Ying,Lv Shi-Wen,Wang Jin,Liu Jing-Min,Wang Shuo Advanced healthcare materials It is of great significance to eliminate excessive reactive oxygen species (ROS) for treating inflammatory bowel disease (IBD). Herein, for the first time, a novel nanozyme NiCo O @PVP is constructed via a step-by-step strategy. Noticeably, the existence of oxygen vacancy in the NiCo O @PVP is helpful for capturing oxygenated compounds, while both redox couples of Co /Co and Ni /Ni will offer richer catalytic sites. As expected, the obtained NiCo O @PVP exhibits pH-dependent multiple mimic enzymatic activities. Benefiting from the introduction of polyvinylpyrrolidone (PVP), the NiCo O @PVP possesses good physiological stability and excellent biosafety in stomach and intestines' environment. Meanwhile, the NiCo O @PVP also presents strong scavenging activities to ROS in vitro, including O , H O , as well as OH. Furthermore, a dextran sodium sulfate (DSS)-induced colitis model is established for evaluating the anti-inflammatory activity of NiCo O @PVP in vivo. Based on the size-mediated and charge-mediated mechanisms, the nanozyme can pass through the digestive tract and target the inflamed site for oral-administrated anti-inflammatory therapy. More interestingly, compared with the model group, the expression levels of inflammatory factors (e.g., Interleukin- 6 (IL-6), Interleukin- 1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS)) in colon of mice show a significant decrease after nanozyme intervention, thereby inhibiting the development of IBD. In short, current work provides an alternative therapy for patients suffering from IBD. 10.1002/adhm.202101618
    High-Oxygen Submersion Fetal Thymus Organ Cultures Enable FOXN1-Dependent and -Independent Support of T Lymphopoiesis. Han Jianxun,Zúñiga-Pflücker Juan Carlos Frontiers in immunology T cell development is effectively supported in fetal thymus organ cultures (FTOCs), which places thymus lobes atop an air-liquid interface (ALI) culture system. The direct exposure to air is critical for its success, as fetal thymus lobes placed in low oxygen submersion (LOS)-FTOCs fail to support thymocyte development. However, submersion cultures performed in the presence of high concentration of ambient oxygen (60~80%) allow for normal thymocyte development, but the underlying mechanism for this rescue has remained elusive. Here, we show that FOXN1 expression in thymic epithelial cells (TECs) from LOS-FTOCs was greatly reduced compared to conventional ALI-FTOCs. Consequently, the expression of important FOXN1 target genes, including and , in TECs was extinguished. The loss of DLL4 and CCL25 interrupted thymocyte differentiation and led to CD4CD8 cells exiting the lobes, respectively. High oxygen submersion (HOS)-FTOCs restored the expression of FOXN1 and its target genes, as well as maintained high levels of MHCII expression in TECs. In addition, HOS-FTOCs promoted the self-renewal of CD4CD8CD44CD25 cells, allowing for the continuous generation of later stage thymocytes. Forced FOXN1 expression in TECs rescued thymocyte developmental progression, but not cellularity, in LOS-FTOCs. Given that oxidative stress has been reported to accelerate the onset of age-associated thymic involution, we postulate that regulation of FOXN1 by oxygen and antioxidants may underpin this biological process. 10.3389/fimmu.2021.652665
    Effects of oxygen levels and a Lactobacillus plantarum strain on mortality and immune response of chickens at high altitude. Wang Lihong,Fu Guanhua,Liu Suozhu,Li Long,Zhao Xin Scientific reports Chickens reared in high altitude regions suffer from a high mortality, possibly due to poor immune responses induced by hypoxia. This experiment was conducted to evaluate whether increasing the oxygen level or administration of a probiotic could improve mortality and immune response of chickens at high altitude (2,986 m above the sea level). One-d-old chickens were randomly allocated to 1 of 6 treatments in a 2 × 3 factorial arrangement. The first factor was the oxygen level (low and high), while the second factor was the diet (basal diet, basal diet containing aureomycin, and basal diet plus L. plantarum). Increasing the oxygen level significantly reduced the mortality and improved immune responses. The levels of IgA, IgG, IL-10 and anti-BSA antibodies were significantly higher, while IL-1β, LITAF were significantly lower in chickens reared in the high-oxygen room. In the low-oxygen room, L. plantarum significantly decreased the mortality of chickens compared with the other 2 groups. Moreover, L. plantarum significantly increased the levels of IgA, anti-BSA antibodies, IL-10 and decreased IL-1β, LITAF compared with the control group. These results demonstrated that increasing oxygen level or administration of L. plantarum can improve health status of chickens in high altitude regions. 10.1038/s41598-019-52514-w
    High-Flow Nasal Cannula Compared With Conventional Oxygen Therapy or Noninvasive Ventilation Immediately Postextubation: A Systematic Review and Meta-Analysis. Granton David,Chaudhuri Dipayan,Wang Dominic,Einav Sharon,Helviz Yigal,Mauri Tommaso,Mancebo Jordi,Frat Jean-Pierre,Jog Sameer,Hernandez Gonzalo,Maggiore Salvatore M,Hodgson Carol L,Jaber Samir,Brochard Laurent,Trivedi Vatsal,Ricard Jean-Damien,Goligher Ewan C,Burns Karen E A,Rochwerg Bram Critical care medicine OBJECTIVES:Reintubation after failed extubation is associated with increased mortality and longer hospital length of stay. Noninvasive oxygenation modalities may prevent reintubation. We conducted a systematic review and meta-analysis to determine the safety and efficacy of high-flow nasal cannula after extubation in critically ill adults. DATA SOURCES:We searched MEDLINE, EMBASE, and Web of Science. STUDY SELECTION:We included randomized controlled trials comparing high-flow nasal cannula to other noninvasive methods of oxygen delivery after extubation in critically ill adults. DATA EXTRACTION:We included the following outcomes: reintubation, postextubation respiratory failure, mortality, use of noninvasive ventilation, ICU and hospital length of stay, complications, and comfort. DATA SYNTHESIS:We included eight randomized controlled trials (n = 1,594 patients). Compared with conventional oxygen therapy, high-flow nasal cannula decreased reintubation (relative risk, 0.46; 95% CI, 0.30-0.70; moderate certainty) and postextubation respiratory failure (relative risk, 0.52; 95% CI, 0.30-0.91; very low certainty), but had no effect on mortality (relative risk, 0.93; 95% CI, 0.57-1.52; moderate certainty), or ICU length of stay (mean difference, 0.05 d fewer; 95% CI, 0.83 d fewer to 0.73 d more; high certainty). High-flow nasal cannula may decrease use of noninvasive ventilation (relative risk, 0.64; 95% CI, 0.34-1.22; moderate certainty) and hospital length of stay (mean difference, 0.98 d fewer; 95% CI, 2.16 d fewer to 0.21 d more; moderate certainty) compared with conventional oxygen therapy, however, certainty was limited by imprecision. Compared with noninvasive ventilation, high-flow nasal cannula had no effect on reintubation (relative risk, 1.16; 95% CI, 0.86-1.57; low certainty), mortality (relative risk, 1.12; 95% CI, 0.82-1.53; moderate certainty), or postextubation respiratory failure (relative risk, 0.82; 95% CI, 0.48-1.41; very low certainty). High-flow nasal cannula may reduce ICU length of stay (moderate certainty) and hospital length of stay (moderate certainty) compared with noninvasive ventilation. CONCLUSIONS:High-flow nasal cannula reduces reintubation compared with conventional oxygen therapy, but not compared with noninvasive ventilation after extubation. 10.1097/CCM.0000000000004576
    Effect of high-flow nasal oxygen use on oxygen flow at the surgical site: a pilot study. Seki Hiroyuki,Fukagata Koji,Ito Shingo,Okada Reina,Ouchi Takashi British journal of anaesthesia 10.1016/j.bja.2021.08.024
    Performance of Different Active Humidification Systems in High-Flow Oxygen Therapy. Plotnikow Gustavo A,Villalba Darío,Gogniat Emiliano,Quiroga Corina,Pérez Calvo Eliana,Scapellato José Luis Respiratory care BACKGROUND:We sought to evaluate the performance in terms of absolute humidity (AH), relative humidity (RH), and temperature of different heated humidifiers (HH) and circuits that are commonly used to deliver high-flow oxygen therapy in conventional ranges (30-60 L/min) and unconventional ranges (70-100 L/min). METHODS:In this prospective, observational study, an electronic thermohygrometer was used to obtain the required measurements. A mechanical ventilator was used as a source for high-flow nasal cannula oxygen therapy. For active humidification, the following equipment was used: a HH with standard disposable water trap circuit, 3 servo-controlled HH, and 7 circuits with a heated wire. Data on environmental conditions (ie, temperature, RH, AH) were collected from the laboratory during each measurement; the temperature, RH, and AH resulting from the application of 8 flows (30-100 L/min) were also recorded. Variables were compared with analysis of variance for repeated measurements with Tukey post hoc tests. A value of < .05 was assumed to be significant. RESULTS:During the study, a statistically significant difference was found in the average AH for each flow for the different devices ( < .005). The highest AH values were recorded with the Fisher & Paykel MR850 and the Medtronic-DAR circuit (AH = 40.8 mg/L with flow of 50 L/min, < .005), and the lowest AH values were recorded with the Flexicare FL9000 HH and the Flexicare circuit (AH = 11.4 mg/L with 100 L/min flow, < .005). For flows > 50 L/min, the best performance for all flows in terms of AH was found with the Fisher & Paykel MR850 HH, regardless of the circuit used. CONCLUSIONS:During oxygen therapy with very high gas flows, HH devices behave differently and in many cases are inefficient in delivering adequate humidification, even at conventional flows. Caution is therefore recommended when selecting the device and flow settings for the implementation of high-flow nasal cannula oxygen therapy. 10.4187/respcare.07654
    High-frequency vs. conventional ventilation at the time of CDH repair is not associated with higher mortality and oxygen dependency: a retrospective cohort study. Derraugh Gabrielle,Levesque Matthew,Schantz Daryl,Sesha Molly,Minski John,Baier John,Morris Melanie I,Shawyer Anna C,Balshaw Robert,Lum Min Suyin A,Keijzer Richard Pediatric surgery international PURPOSE:The VICI-trial reported that in patients with congenital diaphragmatic hernia (CDH), mortality or bronchopulmonary dysplasia (BPD) were equivalent using conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation. The purpose of this study was to determine if the mode of ventilation at the time of CDH repair affected mortality or oxygen dependence at 28 days. METHODS:We performed a retrospective cohort study of infants born wih CDH from 1991 to 2015. A generalized linear model was applied to the data using a propensity score analysis. RESULTS:Eighty patients met the inclusion criteria; at the time of surgery 39 (48.8%) patients were on HFV and 41 (51.3%) patients were on CMV. In the HFV group, 16 (47.1%) patients remained oxygen dependent and there were 5 (12.8%) deaths at 28 days. In the CMV group, 5 (12.2%) patients remained oxygen dependent at 28 days but none had died. The base model demonstrated that the HFV group had increased rates of oxygen dependence [OR = 6.40 (2.13, 22.2), p = 0.002]. However, after propensity score analysis, we found no difference between HFV and CMV. CONCLUSION:Our study suggests that in infants with CDH, there is no significant difference between HFV and CMV in oxygen dependency or death. 10.1007/s00383-020-04740-x
    Necrostatin-1 prolongs latency to convulsion in mice exposed to high oxygen partial pressure. Diving and hyperbaric medicine INTRODUCTION:Exposure to very high oxygen partial pressure may cause central nervous system oxygen toxicity (CNS-OT). The role of necroptosis in the pathogenesis of CNS-OT is still unclear. METHODS:In experiment one, male C57BL/6 mice in the oxygen toxicity (OT) group (n = 5) and necrostatin-1 (Nec-1; a necroptosis inhibitor) (1.5 mg·kg-1, intraperitoneal) group (n = 5) were exposed to pure oxygen at 600 kPa, and the latency to tonic-clonic seizure was recorded. In experiment two, mice were divided into three groups: control group (n = 11), OT group (n = 12) and Nec-1 group (n = 12). Nec-1 was intraperitoneally administered 30 min before oxygen exposure. Mice in the OT group and Nec-1 group were exposed to pure oxygen at 400 kPa for 30 min, and then sacrificed; the brain was harvested for the assessment of inflammation, oxidative stress and necroptosis. RESULTS:Experiment one. Nec-1 pre-treatment significantly prolonged the latency to seizure (245 [SD 18] seconds in the OT group versus 336 (34) seconds in the Nec-1 group). Experiment two. Nec-1 pre-treatment markedly reduced inflammatory cytokines and inhibited cerebral necroptosis, but failed to significantly suppress cerebral oxidative stress. CONCLUSIONS:These findings indicate necroptosis is involved in the pathogenesis of CNS-OT, and inhibition of necroptosis may prolong seizure latency, but the specific mechanisms should be investigated further. 10.28920/dhm51.2.134-139
    Comparison of hypoxemia, intubation procedure, and complications for non-invasive ventilation against high-flow nasal cannula oxygen therapy for patients with acute hypoxemic respiratory failure: a non-randomized retrospective analysis for effectiveness and safety (NIVaHIC-aHRF). Zhang Chao,Ou Min BMC emergency medicine BACKGROUND:Optimization of preoxygenation procedure can help to secure the method of intubation by reducing the risks of severe hypoxemia and other problems. There is confusion for efficacy of non-invasive ventilation compared to high-flow oxygen therapy regarding occurrence of severe hypoxemia during the intubation procedure. The purpose of the study was to compare the difference between noninvasive ventilation and high flow oxygen therapy to prevent desaturation during laryngoscopy. METHODS:Patients underwent high-flow nasal cannula oxygen therapy (HCO cohort, n = 161) or non-invasive ventilation procedure (NIV cohort, n = 154) for oxygenation and ventilation due to acute hypoxemic respiratory failure in the intensive care unit. Data before preoxygenation, preoxygenation, intubation, laryngoscopy, and complications of patients due to tracheal intubation were retrospectively collected and analyzed. RESULTS:There was no difference between both cohorts for the demographical and clinical conditions of the patients before preoxygenation (p > 0.05 for all parameters), numbers of patients with severe hypoxia during the intubation procedure (35 vs. 45, p = 0.303), the time duration of laryngoscopy (p = 0.847), number of laryngoscopies attempts (p = 0.804), and immediate and late complications during the intubation procedure. The values of pulse oximetry were reported higher for patients of NIV cohort than those of HCO cohort during preoxygenation. Fewer numbers of patients were reported with severe hypoxia among patients of the NIV cohort than those of the HCO cohort (24 vs., 40, p = 0.042) who have moderate-to-severe hypoxemia (partial pressure of arterial oxygen to fraction of inspired oxygen ratio ≤ 200 mmHg) before preoxygenation. The most common complications were hypertension, pulmonary aspiration, and increased 30-day mortality. CONCLUSIONS:When compared, there was no difference between non-invasive ventilation technique and high-flow oxygen therapy to minimize severe hypoxia prior to laryngoscopy and endotracheal intubation in patients with acute respiratory failure. 10.1186/s12873-021-00402-w
    Effect of Postextubation High-Flow Nasal Oxygen With Noninvasive Ventilation vs High-Flow Nasal Oxygen Alone on Reintubation Among Patients at High Risk of Extubation Failure: A Randomized Clinical Trial. Thille Arnaud W,Muller Grégoire,Gacouin Arnaud,Coudroy Rémi,Decavèle Maxens,Sonneville Romain,Beloncle François,Girault Christophe,Dangers Laurence,Lautrette Alexandre,Cabasson Séverin,Rouzé Anahita,Vivier Emmanuel,Le Meur Anthony,Ricard Jean-Damien,Razazi Keyvan,Barberet Guillaume,Lebert Christine,Ehrmann Stephan,Sabatier Caroline,Bourenne Jeremy,Pradel Gael,Bailly Pierre,Terzi Nicolas,Dellamonica Jean,Lacave Guillaume,Danin Pierre-Éric,Nanadoumgar Hodanou,Gibelin Aude,Zanre Lassane,Deye Nicolas,Demoule Alexandre,Maamar Adel,Nay Mai-Anh,Robert René,Ragot Stéphanie,Frat Jean-Pierre, JAMA Importance:High-flow nasal oxygen may prevent postextubation respiratory failure in the intensive care unit (ICU). The combination of high-flow nasal oxygen with noninvasive ventilation (NIV) may be an optimal strategy of ventilation to avoid reintubation. Objective:To determine whether high-flow nasal oxygen with prophylactic NIV applied immediately after extubation could reduce the rate of reintubation, compared with high-flow nasal oxygen alone, in patients at high risk of extubation failure in the ICU. Design, Setting, and Participants:Multicenter randomized clinical trial conducted from April 2017 to January 2018 among 641 patients at high risk of extubation failure (ie, older than 65 years or with an underlying cardiac or respiratory disease) at 30 ICUs in France; follow-up was until April 2018. Interventions:Patients were randomly assigned to high-flow nasal oxygen alone (n = 306) or high-flow nasal oxygen alternating with NIV (n = 342) immediately after extubation. Main Outcomes and Measures:The primary outcome was the proportion of patients reintubated at day 7; secondary outcomes included postextubation respiratory failure at day 7, reintubation rates up until ICU discharge, and ICU mortality. Results:Among 648 patients who were randomized (mean [SD] age, 70 [10] years; 219 women [34%]), 641 patients completed the trial. The reintubation rate at day 7 was 11.8% (95% CI, 8.4%-15.2%) (40/339) with high-flow nasal oxygen and NIV and 18.2% (95% CI, 13.9%-22.6%) (55/302) with high-flow nasal oxygen alone (difference, -6.4% [95% CI, -12.0% to -0.9%]; P = .02). Among the 11 prespecified secondary outcomes, 6 showed no significant difference. The proportion of patients with postextubation respiratory failure at day 7 (21% vs 29%; difference, -8.7% [95% CI, -15.2% to -1.8%]; P = .01) and reintubation rates up until ICU discharge (12% vs 20%, difference -7.4% [95% CI, -13.2% to -1.8%]; P = .009) were significantly lower with high-flow nasal oxygen and NIV than with high-flow nasal oxygen alone. ICU mortality rates were not significantly different: 6% with high-flow nasal oxygen and NIV and 9% with high-flow nasal oxygen alone (difference, -2.4% [95% CI, -6.7% to 1.7%]; P = .25). Conclusions and Relevance:In mechanically ventilated patients at high risk of extubation failure, the use of high-flow nasal oxygen with NIV immediately after extubation significantly decreased the risk of reintubation compared with high-flow nasal oxygen alone. Trial Registration:ClinicalTrials.gov Identifier: NCT03121482. 10.1001/jama.2019.14901
    Oxygen Enrichment Mitigates High-Altitude Hypoxia-Induced Hippocampal Neurodegeneration and Memory Dysfunction Associated with Attenuated Tau Phosphorylation. Cai Jing,Ruan Junyong,Shao Xi,Ding Yuanjun,Xie Kangning,Tang Chi,Yan Zedong,Luo Erping,Jing Da High altitude medicine & biology Cai, Jing, Junyong Ruan, Xi Shao, Yuanjun Ding, Kangning Xie, Chi Tang, Zedong Yan, Erping Luo, and Da Jing. Oxygen enrichment mitigates high-altitude hypoxia-induced hippocampal neurodegeneration and memory dysfunction associated with attenuated tau phosphorylation. . 22:274-284, 2021. Brain is predominantly vulnerable to high-altitude hypoxia (HAH), resulting in neurodegeneration and cognitive impairment. The technology of oxygen enrichment has proven effective to decrease the heart rate and improve the arterial oxygen saturation by reducing the equivalent altitude. However, the efficacy of oxygen enrichment on HAH-induced cognitive impairments remains controversial based on the results of neuropsychological tests, and its role in HAH-induced hippocampal morphological and molecular changes remains unknown. Therefore, this study aims to systematically investigate the effects of oxygen enrichment on the memory dysfunction and hippocampal neurodegeneration caused by HAH. Fifty-one male Sprague-Dawley rats were equally assigned to three groups: normal control, HAH, and HAH with oxygen enrichment (HAHO). Rats in the HAH and HAHO groups were exposed to hypoxia for 3 days in a hypobaric hypoxia chamber at a simulated altitude of 6,000 m. Rats in the HAHO group were supplemented with oxygen-enriched air, with 12 hours/day in the hypobaric hypoxia chamber. Our results showed that oxygen enrichment improved the locomotor activity of HAH-exposed rats. The Morris water maze test revealed that oxygen enrichment significantly ameliorated HAH-induced spatial memory deficits. Oxygen enrichment also improved morphological alterations of pyramidal cells and the ultrastructure of neurons in the hippocampal CA1 region in rats exposed to acute HAH. Tau hyperphosphorylation at Ser396, Ser262, Thr231, and Thr181 was also significantly attenuated by oxygen enrichment in HAH-exposed rats. Together, our study reveals that oxygen enrichment can ameliorate HAH-induced cognitive impairments associated with improved hippocampal morphology and molecular expression, and highlights that oxygen enrichment may become a promising alternative treatment against neurodegeneration for humans ascending to the plateau. 10.1089/ham.2020.0218
    Outcomes of delivery room resuscitation of bradycardic preterm infants: A retrospective cohort study of randomised trials of high vs low initial oxygen concentration and an individual patient data analysis. Kapadia Vishal,Oei Ju Lee,Finer Neil,Rich Wade,Rabi Yacov,Wright Ian M,Rook Denise,Vermeulen Marijn J,Tarnow-Mordi William O,Smyth John P,Lui Kei,Brown Steven,Saugstad Ola D,Vento Maximo Resuscitation OBJECTIVE:To determine whether hospital mortality (primary outcome) is associated with duration of bradycardia without chest compressions during delivery room (DR) resuscitation in a retrospective cohort study of randomized controlled trials (RCTs) in preterm infants assigned low versus high initial oxygen concentration. METHODS:Medline and EMBASE were searched from 01/01/1990 to 12/01/2020. RCTs of low vs high initial oxygen concentration which recorded serial heart rate (HR) and oxygen saturation (SpO) during resuscitation of infants <32 weeks gestational age were eligible. Individual patient level data were requested from the authors. Newborns receiving chest compressions in the DR and those with no recorded HR in the first 2 min after birth were excluded. Prolonged bradycardia (PB) was defined as HR < 100 bpm for ≥2 min. Individual patient data analysis and pooled data analysis were conducted. RESULTS:Data were collected from 720 infants in 8 RCTs. Neonates with PB had higher odds of hospital death before [OR 3.8 (95% CI 1.5, 9.3)] and after [OR 1.7 (1.2, 2.5)] adjusting for potential confounders. Bradycardia occurred in 58% infants, while 38% had PB. Infants with bradycardia were more premature and had lower birth weights. The incidence of bradycardia in infants resuscitated with low (≤30%) and high (≥60%) oxygen was similar. Neonates with both, PB and SpO < 80% at 5 min after birth had higher odds of hospital mortality. [OR 18.6 (4.3, 79.7)]. CONCLUSION:In preterm infants who did not receive chest compressions in the DR, prolonged bradycardia is associated with hospital mortality. 10.1016/j.resuscitation.2021.08.023
    Early oxygen levels contribute to brain injury in extremely preterm infants. Rantakari Krista,Rinta-Koski Olli-Pekka,Metsäranta Marjo,Hollmén Jaakko,Särkkä Simo,Rahkonen Petri,Lano Aulikki,Lauronen Leena,Nevalainen Päivi,Leskinen Markus J,Andersson Sture Pediatric research BACKGROUND:Extremely low gestational age newborns (ELGANs) are at risk of neurodevelopmental impairments that may originate in early NICU care. We hypothesized that early oxygen saturations (SpO), arterial pO levels, and supplemental oxygen (FiO) would associate with later neuroanatomic changes. METHODS:SpO, arterial blood gases, and FiO from 73 ELGANs (GA 26.4 ± 1.2; BW 867 ± 179 g) during the first 3 postnatal days were correlated with later white matter injury (WM, MRI, n = 69), secondary cortical somatosensory processing in magnetoencephalography (MEG-SII, n = 39), Hempel neurological examination (n = 66), and developmental quotients of Griffiths Mental Developmental Scales (GMDS, n = 58). RESULTS:The ELGANs with later WM abnormalities exhibited lower SpO and pO levels, and higher FiO need during the first 3 days than those with normal WM. They also had higher pCO values. The infants with abnormal MEG-SII showed opposite findings, i.e., displayed higher SpO and pO levels and lower FiO need, than those with better outcomes. Severe WM changes and abnormal MEG-SII were correlated with adverse neurodevelopment. CONCLUSIONS:Low oxygen levels and high FiO need during the NICU care associate with WM abnormalities, whereas higher oxygen levels correlate with abnormal MEG-SII. The results may indicate certain brain structures being more vulnerable to hypoxia and others to hyperoxia, thus emphasizing the role of strict saturation targets. IMPACT:This study indicates that both abnormally low and high oxygen levels during early NICU care are harmful for later neurodevelopmental outcomes in preterm neonates. Specific brain structures seem to be vulnerable to low and others to high oxygen levels. The findings may have clinical implications as oxygen is one of the most common therapies given in NICUs. The results emphasize the role of strict saturation targets during the early postnatal period in preterm infants. 10.1038/s41390-021-01460-3
    Oxidative Stress-Induced Damage to the Developing Hippocampus Is Mediated by GSK3β. The Journal of neuroscience : the official journal of the Society for Neuroscience Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 β activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 β during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage. Premature infants are especially vulnerable to oxidative stress, as their antioxidant defenses are underdeveloped. Indeed, high oxygen tension is associated with poor neurologic outcomes. Because of its sustained postnatal development and role in learning and memory, the hippocampus is especially vulnerable to oxidative damage in premature infants. However, the role of oxidative stress in the developing hippocampus has yet to be explored. With ever-rising rates of neonatal brain injury and no universally viable approach to maximize functional recovery, a better understanding of the mechanisms underlying neonatal brain injury is needed. Addressing this need, this study uses perinatal hyperoxia to study cognitive deficits, pathophysiology, and molecular mechanisms of oxidative damage in the developing hippocampus. 10.1523/JNEUROSCI.2389-21.2022
    Comparative study of brain damage and oxidative stress using two animal models of the shaken baby syndrome. Experimental gerontology The objective was compare the morphological damages in brain and to evaluate the participation of oxidative stress, using two animal models of shaken baby syndrome (SBS). Five-day-old Wistar rats were used to develop two models of SBS as follows: Gyrotwister (GT) group was subjected to low intensity, high duration rotating movements and Ratshaker (RS) group made to undergo high intensity, low duration anteroposterior movements. Both groups presented respiratory distress, weight loss and shorter stature compared with the control group. In addition, involuntary movements occurred in both experimental models. Hemorrhage was observed in 10 % of the GT group and in 40 % of the RS group. This last group experienced lesser weight gain at 30 days. Glutathione decreased by 25.7 % (GT) and 59.96 (RT). Cell data analysis revealed the presence of crenate and pyknotic cells, characterized by apparent absence of nucleus and nucleolus as well as vacuolation in the GT group. In the RS group, there were a high number of angular, pyknotic and shrunken cells, and a lot of vacuolization. The severity of the brain damage can be related to the magnitude of biochemical modifications, specifically, those related to the production of reactive oxygen or nitrogen species, oxidative stress, oxidative damage. 10.1016/j.exger.2022.111874