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Experimental Physiology Dec 2019• What is the topic of this review? To explore the unique evolutionary origins of the human brain and critically appraise its energy budget, including limits of oxygen... (Review)
Review
NEW FINDINGS
• What is the topic of this review? To explore the unique evolutionary origins of the human brain and critically appraise its energy budget, including limits of oxygen and glucose deprivation during anoxia and ischaemia. • What advances does it highlight? The brain appears to be more resilient to substrate depletion than traditionally thought, highlighting greater resilience and an underappreciated capacity for functional recovery.
ABSTRACT
The human brain has evolved into an unusually large, complex and metabolically expensive organ that relies entirely on a continuous supply of O and glucose. It has traditionally been assumed that its exorbitant energy budget, combined with little to no energy reserves, renders it especially vulnerable to anoxia and ischaemia, with substrate depletion and progression towards cell death largely irreversible and rapid. However, new and exciting evidence suggests that neurons can survive for longer than previously thought, highlighting an unexpected resilience and underappreciated capacity for functional recovery that has changed the way we think about brain cell death. Nature has the potential to unlock some of the mysteries underlying ischaemic survival, with select vertebrates having solved the problem of anoxia-hypoxia tolerance over millions of years of evolution. Better understanding of their survival strategies, including remarkable adaptations in brain physiology and redox homeostasis, might help to identify new therapeutic targets for human diseases characterized by O deprivation, ischaemia-reperfusion injury and ageing.
Topics: Adaptation, Physiological; Animals; Brain Death; Energy Metabolism; Glucose; Humans; Hypoxia; Oxygen
PubMed: 31605408
DOI: 10.1113/EP088005 -
Ageing Research Reviews Sep 2023Alzheimer's disease (AD) is characterized by an adverse cellular environment and pathological alterations in distinct brain regions. The development is triggered or... (Review)
Review
Alzheimer's disease (AD) is characterized by an adverse cellular environment and pathological alterations in distinct brain regions. The development is triggered or facilitated by a condition such as hypoxia or ischemia, or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Increasing evidence suggests that hypoxia may affect many pathological aspects of AD, including oxidative stress, mitochondrial dysfunction, ER stress, amyloidogenic processing of APP, and Aβ accumulation, which may collectively result in neurodegeneration. Further investigation into the relationship between hypoxia and AD may provide an avenue for the effective preservation and pharmacological treatment of this neurodegenerative disease. This review summarizes the effects of normoxia and hypoxia on AD pathogenesis and discusses the underlying mechanisms. Regulation of HIF-1α and the role of its key players, including P53, VEGF, and GLUT1, are also discussed.
Topics: Humans; Neurodegenerative Diseases; Alzheimer Disease; Hypoxia; Brain; Oxidative Stress
PubMed: 37490963
DOI: 10.1016/j.arr.2023.102022 -
Seminars in Fetal & Neonatal Medicine Apr 2020The premature infant is to some extent protected from hypoxia, however defense against hyperoxia is poorly developed. The optimal assessment of oxygenation is to measure... (Review)
Review
The premature infant is to some extent protected from hypoxia, however defense against hyperoxia is poorly developed. The optimal assessment of oxygenation is to measure oxygen delivery and extraction. At the bedside PaO and SpO are approximations of oxygenation at the tissue level. After birth asphyxia it is crucial to know whether or not to give oxygen supplementation, when, how much, and for how long. Oxygen saturation targets in the delivery room have been studied, but the optimal targets might still be unknown because factors like gender and delayed cord clamping influence saturation levels. However, SpO > 80% at 5 min of age is associated with favorable long term outcome in preterm babies. Immature infants most often need oxygen supplementation beyond the delivery room. Predefined saturation levels, and narrow alarm limits together with the total oxygen exposure may impact on development of oxygen related diseases like ROP and BPD. Hyperoxia is a strong trigger for genetic and epigenetic changes, contributing to the development of these conditions and perhaps lifelong changes.
Topics: Humans; Hyperoxia; Hypoxia; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Oximetry; Oxygen; Oxygen Inhalation Therapy
PubMed: 32037265
DOI: 10.1016/j.siny.2020.101078 -
Progress in Neurobiology Oct 2017Sublethal hypoxic or ischemic events can improve the tolerance of tissues, organs, and even organisms from subsequent lethal injury caused by hypoxia or ischemia. This... (Review)
Review
Sublethal hypoxic or ischemic events can improve the tolerance of tissues, organs, and even organisms from subsequent lethal injury caused by hypoxia or ischemia. This phenomenon has been termed hypoxic or ischemic preconditioning (HPC or IPC) and is well established in the heart and the brain. This review aims to discuss HPC and IPC with respect to their historical development and advancements in our understanding of the neurochemical basis for their neuroprotective role. Through decades of collaborative research and studies of HPC and IPC in other organ systems, our understanding of HPC and IPC-induced neuroprotection has expanded to include: early- (phosphorylation targets, transporter regulation, interfering RNA) and late- (regulation of genes like EPO, VEGF, and iNOS) phase changes, regulators of programmed cell death, members of metabolic pathways, receptor modulators, and many other novel targets. The rapid acceleration in our understanding of HPC and IPC will help facilitate transition into the clinical setting.
Topics: Animals; Humans; Hypoxia; Ischemia; Ischemic Preconditioning; Neuroprotection
PubMed: 28110083
DOI: 10.1016/j.pneurobio.2017.01.001 -
Microbes and Infection Mar 2017Inflammatory bowel disease (IBD) is a general term to describe inflammatory diseases of the gastrointestinal tract such as Crohn's disease and ulcerative colitis. IBD... (Review)
Review
Inflammatory bowel disease (IBD) is a general term to describe inflammatory diseases of the gastrointestinal tract such as Crohn's disease and ulcerative colitis. IBD affects approximately 1 in 200 individuals and exerts a significant health and quality of life burden on patients. Surgical intervention can be curative in ulcerative colitis but there is currently no cure for Crohn's disease. Since this is the case, and the fact that patients are often diagnosed at a young age, IBD exerts a significant financial burden on the health care system, and society as a whole. The underlying pathology of IBD is complex and involves a combination of genetic, environmental and microbial factors. Regardless of the underlying causes of the condition, this disease is universally characterized by disruption to the protective epithelial barrier separating the intestinal lumen above from the mucosal immune system below. Once this barrier becomes compromised a sequence of events ensues, that can occur in repetitive cycles to ensure long-term and serious damage to the gut. The role of hypoxia and hypoxia-dependent signalling pathways are increasingly appreciated to play a role in the physiology and pathophysiology of the intestine. The intestinal epithelium normally exists in a state of physiological hypoxia, with additional tissue hypoxia a feature of active inflammatory disease. Furthermore, recent pre-clinical animal studies have clearly supported the rationale for pharmacologically manipulating the oxygen-sensitive hypoxia-inducible factor (HIF) pathway in models of IBD. Thus, this review will discuss the contribution of hypoxia sensitive pathways in the pathology of IBD. Finally we will discuss the emerging evidence for manipulation of hypoxia-sensitive pathways in the treatment of IBD.
Topics: Animals; Humans; Hypoxia; Inflammatory Bowel Diseases
PubMed: 27664046
DOI: 10.1016/j.micinf.2016.09.004 -
Annual Review of Medicine Jan 2022In order to fuel their relentless expansion, cancers must expand their vasculature to augment delivery of oxygen and essential nutrients. The disordered web of irregular... (Review)
Review
In order to fuel their relentless expansion, cancers must expand their vasculature to augment delivery of oxygen and essential nutrients. The disordered web of irregular vessels that results, however, leaves gaps in oxygen delivery that foster tumor hypoxia. At the same time, tumor cells increase their oxidative metabolism to cope with the energetic demands of proliferation, which further worsens hypoxia due to heightened oxygen consumption. In these hypoxic, nutrient-deprived environments, tumors and suppressive stroma evolve to flourish while antitumor immunity collapses due to a combination of energetic deprivation, toxic metabolites, acidification, and other suppressive signals. Reversal of cancer hypoxia thus has the potential to increase the survival and effector function of tumor-infiltrating T cells, as well as to resensitize tumors to immunotherapy. Early clinical trials combining hypoxia reduction with immune checkpoint blockade have shown promising results in treating patients with advanced, metastatic, and therapeutically refractory cancers.
Topics: Humans; Hypoxia; Immunotherapy; Neoplasms; T-Lymphocytes; Tumor Microenvironment
PubMed: 34699264
DOI: 10.1146/annurev-med-060619-022830 -
Experimental Neurology Jun 2021Therapeutic hypothermia (TH) is well established as a standard treatment for term and near-term infants. However, therapeutic effects of hypothermia following neonatal...
Therapeutic hypothermia (TH) is well established as a standard treatment for term and near-term infants. However, therapeutic effects of hypothermia following neonatal anoxia in very premature babies remains inconclusive. The present rodent model of preterm neonatal anoxia has been shown to alter developmental milestones and hippocampal neurogenesis, and to disrupt spatial learning and memory in adulthood. These effects seem to be reduced by post-insult hypothermia. Epigenetic-related mechanisms have been postulated as valuable tools for developing new therapies. Dentate gyrus neurogenesis is regulated by epigenetic factors. This study evaluated whether TH effects in a rodent model of preterm oxygen deprivation are based on epigenetic alterations. The effects of TH on both developmental features (somatic growth, maturation of physical characteristics and early neurological reflexes) and performance of behavioral tasks at adulthood (spatial reference and working memory, and fear conditioning) were investigated in association with the possible involvement of the epigenetic operator Enhancer of zeste homolog 2 (Ezh2), possibly related to long-lasting effects on hippocampal neurogenesis. Results showed that TH reduced both anoxia-induced hippocampal neurodegeneration and anoxia-induced impairments on risk assessment behavior, acquisition of spatial memory, and extinction of auditory and contextual fear conditioning. In contrast, TH did not prevent developmental alterations caused by neonatal anoxia and did not restore hippocampal neurogenesis or cause changes in EZH2 levels. In conclusion, despite the beneficial effects of TH in hippocampal neurodegeneration and in reversing disruption of performance of behavioral tasks following oxygen deprivation in prematurity, these effects seem not related to developmental alterations and hippocampal neurogenesis and, apparently, is not caused by Ezh2-mediated epigenetic alteration.
Topics: Animals; Animals, Newborn; Female; Hippocampus; Hypothermia, Induced; Hypoxia, Brain; Lactation; Male; Rats; Rats, Wistar; Spatial Memory; Treatment Outcome
PubMed: 33713657
DOI: 10.1016/j.expneurol.2021.113691 -
Cell and Tissue Research Sep 2016Hypoxia and hypoxia signalling through the transcription factor hypoxia inducible factor-1 (HIF-1), play an important role in normal tissue repair processes. Tissue... (Review)
Review
Hypoxia and hypoxia signalling through the transcription factor hypoxia inducible factor-1 (HIF-1), play an important role in normal tissue repair processes. Tissue injury generally produces at least the transient loss of normal vascular perfusion and the resulting hypoxia induces the expression of many genes that allow the tissue to adapt to hypoxia, to start the repair process and, in time, to re-establish oxygen delivery to the tissue. In most cases, transient hypoxia and the activation of the HIF-1 pathway are beneficial and promote the repair process, producing tissue that might not perfectly reform its original architecture but that has its function substantially restored. However, in some cases of chronic injury, chronic hypoxia and pathological repair, the hypoxia pathway might be responsible for driving the process of fibrosis and can lead to excessive scarring and compromised organ function.
Topics: Animals; Disease; Fibrosis; Humans; Hypoxia; Organ Specificity; Oxygen; Wound Healing
PubMed: 27423661
DOI: 10.1007/s00441-016-2461-3 -
The Journal of Experimental Biology Jul 2020The development of anoxia within tissues represents a significant challenge to most animals because of the decreased capacity for aerobic ATP production, the associated... (Review)
Review
The development of anoxia within tissues represents a significant challenge to most animals because of the decreased capacity for aerobic ATP production, the associated loss of essential cellular functions and the potential for detrimental tissue oxidation upon reoxygenation. Despite these challenges, there are many animals from multiple phyla that routinely experience anoxia and can fully recover. In this Review, we integrate knowledge gained from studies of anoxia-tolerant species across many animal taxa We primarily focus on strategies used to reduce energy requirements, minimize the consequences of anaerobic ATP production and reduce the adverse effects of reactive oxygen species, which are responsible for tissue damage with reoxygenation. We aim to identify common strategies, as well as novel solutions, to the challenges of anoxia exposure. This Review chronologically examines the challenges faced by animals as they enter anoxia, as they attempt to maintain physiological function during prolonged anoxic exposure and, finally, as they emerge from anoxia. The capacity of animals to survive anoxia is also considered in relation to the increasing prevalence of anoxic zones within marine and freshwater environments, and the need to understand what limits survival.
Topics: Animals; Hypoxia; Oxidation-Reduction; Oxygen; Reactive Oxygen Species
PubMed: 32651221
DOI: 10.1242/jeb.207613 -
American Journal of Physiology.... Dec 2014Tissue injury can occur for a variety of reasons, including physical damage, infection, and ischemia. The ability of tissues to effectively recover from injury is a... (Review)
Review
Tissue injury can occur for a variety of reasons, including physical damage, infection, and ischemia. The ability of tissues to effectively recover from injury is a cornerstone of human health. The healing response in tissues is conserved across organs and typically involves distinct but overlapping inflammatory, proliferative, and maturation/resolution phases. If the inflammatory phase is not successfully controlled and appropriately resolved, an excessive healing response characterized by scar formation can lead to tissue fibrosis, a major clinical complication in disorders such as Crohn's disease (CD). As a result of enhanced metabolic and inflammatory processes during chronic inflammation, profound changes in tissue oxygen levels occur leading to localized tissue hypoxia. Therefore, inflammation, fibrosis, and hypoxia are coincidental events during inflammation-driven fibrosis. Our current understanding of the mechanism(s) underpinning fibrosis is limited as are the therapeutic options available. In this review, we discuss what is known about the cellular and molecular mechanisms underpinning inflammation-driven fibrosis and how hypoxia may play a role in shaping this process.
Topics: Animals; Cell Hypoxia; Fibrosis; Humans; Hypoxia; Inflammation; Inflammation Mediators; Oxygen; Signal Transduction; Wound Healing
PubMed: 25298511
DOI: 10.1152/ajpregu.00349.2014