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Physiological Reviews Jan 2002At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At... (Review)
Review
At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish "redox homeostasis." Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman (J Gerontol 11: 298-300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Topics: Aging; Animals; Cell Physiological Phenomena; Disease; Free Radicals; Humans; Oxidation-Reduction; Oxidative Stress; Signal Transduction; Stress, Physiological
PubMed: 11773609
DOI: 10.1152/physrev.00018.2001 -
Minerva Anestesiologica May 2010Following successful resuscitation from cardiac arrest, neurological impairment as well as other types of organ dysfunction still cause significant morbidity and... (Review)
Review
Following successful resuscitation from cardiac arrest, neurological impairment as well as other types of organ dysfunction still cause significant morbidity and mortality. The whole-body ischemia-reperfusion response that occurs during cardiac arrest and subsequent restoration of systemic circulation results in a series of pathophysiological processes that have been termed the post-cardiac arrest syndrome. The components of the post-cardiac arrest syndrome comprise post-cardiac arrest brain injury, post-cardiac arrest myocardial dysfunction, the systemic ischemia-reperfusion response and persistent precipitating pathology. Management of the post-cardiac arrest syndrome involves intensive care support with input from various other medical specialties in a coordinated fashion. Management of ventilation aims for normal carbon dioxide values and normoxia rather than hyperoxia. Management of the circulation commonly requires vasoactive support to overcome (often transient) myocardial dysfunction. Particular attention should be given to evidence of cardiac ischemia and referral for urgent angiography and percutaneous coronary intervention, if appropriate, should be available to all. Optimizing neurological recovery will involve seizure control, management of hyperglycemia and therapeutic hypothermia. Prognostication following cardiac arrest remains difficult, but there are diagnostic tests that may be used with some degree of accuracy.
Topics: Heart Arrest; Humans; Nervous System Diseases; Recovery of Function; Reperfusion Injury; Resuscitation; Syndrome
PubMed: 20395899
DOI: No ID Found -
Blood Apr 2011More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each... (Review)
Review
More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Toll-like receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are fundamental to innate immunity. Of the 11 members of the IL-1 family, IL-1β has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL-1β results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1β is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1β neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1β activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors.
Topics: Animals; Autoimmune Diseases; Disease; Humans; Inflammation; Interleukin-1; Models, Biological; Molecular Targeted Therapy; Multigene Family; Receptors, Interleukin-1; Toll-Like Receptors
PubMed: 21304099
DOI: 10.1182/blood-2010-07-273417 -
Nature Aug 2021The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile... (Review)
Review
The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile genetic elements that can move from one genomic location to another; in this process, they amplify and increase their presence in genomes, sometimes to very high copy numbers. In this Review we discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans. Retrotransposons have been coevolving with their host genomes since the dawn of life. This relationship has been largely competitive, and transposons have earned epithets such as 'junk DNA' and 'molecular parasites'. Much of our knowledge of the evolution of retrotransposons reflects their activity in the germline and is evident from genome sequence data. Recent research has provided a wealth of information on the activity of retrotransposons in somatic tissues during an individual lifespan, the molecular mechanisms that underlie this activity, and the manner in which these processes intersect with our own physiology, health and well-being.
Topics: Aging; Animals; DNA Damage; Disease; Gene Silencing; Genome, Human; Genomics; Humans; Immunity, Innate; Retroelements
PubMed: 34349292
DOI: 10.1038/s41586-021-03542-y -
Physiological Reviews Jan 2007The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in... (Review)
Review
The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.
Topics: Animals; Disease; Health; Humans; Nitric Oxide; Peroxynitrous Acid
PubMed: 17237348
DOI: 10.1152/physrev.00029.2006 -
RNA (New York, N.Y.) Dec 2017RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has... (Review)
Review
RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.
Topics: Animals; Disease; Humans; RNA; RNA Processing, Post-Transcriptional
PubMed: 28855326
DOI: 10.1261/rna.063503.117 -
Annual Review of Clinical Psychology 2005Stressors have a major influence upon mood, our sense of well-being, behavior, and health. Acute stress responses in young, healthy individuals may be adaptive and... (Review)
Review
Stressors have a major influence upon mood, our sense of well-being, behavior, and health. Acute stress responses in young, healthy individuals may be adaptive and typically do not impose a health burden. However, if the threat is unremitting, particularly in older or unhealthy individuals, the long-term effects of stressors can damage health. The relationship between psychosocial stressors and disease is affected by the nature, number, and persistence of the stressors as well as by the individual's biological vulnerability (i.e., genetics, constitutional factors), psychosocial resources, and learned patterns of coping. Psychosocial interventions have proven useful for treating stress-related disorders and may influence the course of chronic diseases.
Topics: Chronic Disease; Disease; Humans; Psychoneuroimmunology; Stress Disorders, Post-Traumatic; Stress Disorders, Traumatic; Stress, Psychological
PubMed: 17716101
DOI: 10.1146/annurev.clinpsy.1.102803.144141 -
Mitochondrion May 2014The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical,... (Review)
Review
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.
Topics: Brain; Disease; Energy Metabolism; Health; Homeostasis; Humans; Metabolic Networks and Pathways; Mitochondria; Stress, Physiological
PubMed: 23981537
DOI: 10.1016/j.mito.2013.08.006 -
Proceedings of the National Academy of... Nov 2014Although major research efforts have focused on how specific components of foodstuffs affect health, relatively little is known about a more fundamental aspect of diet,...
Although major research efforts have focused on how specific components of foodstuffs affect health, relatively little is known about a more fundamental aspect of diet, the frequency and circadian timing of meals, and potential benefits of intermittent periods with no or very low energy intakes. The most common eating pattern in modern societies, three meals plus snacks every day, is abnormal from an evolutionary perspective. Emerging findings from studies of animal models and human subjects suggest that intermittent energy restriction periods of as little as 16 h can improve health indicators and counteract disease processes. The mechanisms involve a metabolic shift to fat metabolism and ketone production, and stimulation of adaptive cellular stress responses that prevent and repair molecular damage. As data on the optimal frequency and timing of meals crystalizes, it will be critical to develop strategies to incorporate those eating patterns into health care policy and practice, and the lifestyles of the population.
Topics: Circadian Rhythm; Disease; Eating; Health Status; Humans; Time Factors
PubMed: 25404320
DOI: 10.1073/pnas.1413965111 -
Nature Reviews. Neuroscience Jan 2008In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the... (Review)
Review
In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.
Topics: Animals; Brain; Cytokines; Depression; Disease; Humans; Immune System; Inflammation
PubMed: 18073775
DOI: 10.1038/nrn2297