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JournalISSN: 0031-9333

Physiological Reviews

About: Physiological Reviews is an academic journal. The journal publishes majorly in the area(s): Receptor & Skeletal muscle. It has an ISSN identifier of 0031-9333. Over the lifetime, 2326 publication(s) have been published receiving 825907 citation(s). The journal is also known as: Physiological reviews & Physiol. rev..

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Topics: Receptor, Skeletal muscle, Hormone ...read more
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Open accessJournal ArticleDOI: 10.1152/PHYSREV.00018.2001
Abstract: 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, how...

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  • FIG. 3. Regulatory events and their dysregulation depend on the magnitude and duration of the change in ROS or reactive nitrogen species (RNS) concentration. ROS and RNS normally occur in living tissues at relatively low steady-state levels. The regulated increase in superoxide or nitric oxide production leads to a temporary imbalance that forms the basis of redox regulation. The persistent production of abnormally large amounts of ROS or RNS, however, may lead to persistent changes in signal transduction and gene expression, which, in turn, may give rise to pathological conditions.
    FIG. 3. Regulatory events and their dysregulation depend on the magnitude and duration of the change in ROS or reactive nitrogen species (RNS) concentration. ROS and RNS normally occur in living tissues at relatively low steady-state levels. The regulated increase in superoxide or nitric oxide production leads to a temporary imbalance that forms the basis of redox regulation. The persistent production of abnormally large amounts of ROS or RNS, however, may lead to persistent changes in signal transduction and gene expression, which, in turn, may give rise to pathological conditions.
  • FIG. 12. Effect of substrate availability on ROS production. Substantial amounts of superoxide are produced at the semiubiquinone component of the mitochondrial electron transport chain. The probability of ROS production is increased if the influx of electrons is high and the consumption of electrons by cytochrome oxidase in the mitochondrial complex IV relatively low. Consumption of electrons is typically low if the proton gradient is high, i.e., if only a few protons are being consumed by the ATP-generating system as a result of relatively high ATP and low ADP concentrations. This condition normally inhibits the glycolytic pathway and the influx of further energy substrates into the mitochondria. At high glucose concentrations, e.g., as a result of inadequate glycogen synthase (GS) activity, this control may be overridden, resulting in increased ROS production. PFK, phosphofructokinase.
    FIG. 12. Effect of substrate availability on ROS production. Substantial amounts of superoxide are produced at the semiubiquinone component of the mitochondrial electron transport chain. The probability of ROS production is increased if the influx of electrons is high and the consumption of electrons by cytochrome oxidase in the mitochondrial complex IV relatively low. Consumption of electrons is typically low if the proton gradient is high, i.e., if only a few protons are being consumed by the ATP-generating system as a result of relatively high ATP and low ADP concentrations. This condition normally inhibits the glycolytic pathway and the influx of further energy substrates into the mitochondria. At high glucose concentrations, e.g., as a result of inadequate glycogen synthase (GS) activity, this control may be overridden, resulting in increased ROS production. PFK, phosphofructokinase.
  • FIG. 4. Schematic model of OxyR activation. The regulatory protein OxyR is activated by the formation of disulfide bridges. This process is mediated either by hydrogen peroxide (H2O2) or by oxidative changes in the intracellular thiol/disulfide redox state.
    FIG. 4. Schematic model of OxyR activation. The regulatory protein OxyR is activated by the formation of disulfide bridges. This process is mediated either by hydrogen peroxide (H2O2) or by oxidative changes in the intracellular thiol/disulfide redox state.
  • FIG. 11. Distinct redox requirements in the induction and execution of signal cascades: hypothetical model. The antigen-responsive signaling cascades of lyphocytes are strongly enhanced by the ROS produced in large quantities by macrophages in the inflammatory environment. Glycolytically active macrophages produce also large amounts of lactate, which, in turn, induces a decrease in the intracellular glutathione level of the lymphocyte. Experiments with Molt-4 cells have shown that the 4-O-tetradecanoylphorbol 13-acetate (TPA)-induced activation of activator protein 1 (AP-1) and nuclear factor kB (NF-kB) DNA-binding activity is inhibited if the cells are subjected to reducing conditions (1 mM dithiothreitol) before TPA treatment but strongly enhanced if the cells are subjected to reducing conditions 1 h after TPA stimulation. Moreover, the proliferative response and the induction of many types of immunological responses are strongly dependent on relatively high intracellular glutathione levels. The delivery of reduced cysteine by certain types of macrophages to the lymphocytes has been shown to play an important role in the maintenance of adequate glutathione levels in lymphocytes.
    FIG. 11. Distinct redox requirements in the induction and execution of signal cascades: hypothetical model. The antigen-responsive signaling cascades of lyphocytes are strongly enhanced by the ROS produced in large quantities by macrophages in the inflammatory environment. Glycolytically active macrophages produce also large amounts of lactate, which, in turn, induces a decrease in the intracellular glutathione level of the lymphocyte. Experiments with Molt-4 cells have shown that the 4-O-tetradecanoylphorbol 13-acetate (TPA)-induced activation of activator protein 1 (AP-1) and nuclear factor kB (NF-kB) DNA-binding activity is inhibited if the cells are subjected to reducing conditions (1 mM dithiothreitol) before TPA treatment but strongly enhanced if the cells are subjected to reducing conditions 1 h after TPA stimulation. Moreover, the proliferative response and the induction of many types of immunological responses are strongly dependent on relatively high intracellular glutathione levels. The delivery of reduced cysteine by certain types of macrophages to the lymphocytes has been shown to play an important role in the maintenance of adequate glutathione levels in lymphocytes.
  • FIG. 7. Functions of ROS in the immunological response against environmental pathogens. The massive production of ROS (oxidative burst) by activated macrophages in the inflammatory environment provides a first line of defense against environmental pathogens. A certain fraction of pathogens, however, may escape this rapid but moderately effective manifestation of “innate immunity” and may generate within a few days a large progeny of pathogens. Antigenic peptides generated within the activated macrophages by the breakdown of pathogens are presented by major histocompatibility complex (MHC) determinants to the antigen receptors (AR) of T lymphocytes. This interaction triggers the proliferation and differentiation of the T cells and leads within a few days to a large progeny of immunological effector cells. The effector cells provide a highly effective and antigen-specific immunological defense. ROS that are concomitantly produced by the activated macrophages in the inflammatory environment enhance the AR-mediated signal cascades and decrease thereby the activation threshold of the T cells. Without this effect, the T lymphocytes would require relatively large concentrations of antigenic peptides and would lose valuable time in their “race” with the proliferating pathogens. In this situation time may be a matter of life or death for the organism.
    FIG. 7. Functions of ROS in the immunological response against environmental pathogens. The massive production of ROS (oxidative burst) by activated macrophages in the inflammatory environment provides a first line of defense against environmental pathogens. A certain fraction of pathogens, however, may escape this rapid but moderately effective manifestation of “innate immunity” and may generate within a few days a large progeny of pathogens. Antigenic peptides generated within the activated macrophages by the breakdown of pathogens are presented by major histocompatibility complex (MHC) determinants to the antigen receptors (AR) of T lymphocytes. This interaction triggers the proliferation and differentiation of the T cells and leads within a few days to a large progeny of immunological effector cells. The effector cells provide a highly effective and antigen-specific immunological defense. ROS that are concomitantly produced by the activated macrophages in the inflammatory environment enhance the AR-mediated signal cascades and decrease thereby the activation threshold of the T cells. Without this effect, the T lymphocytes would require relatively large concentrations of antigenic peptides and would lose valuable time in their “race” with the proliferating pathogens. In this situation time may be a matter of life or death for the organism.
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8,461 Citations


Journal ArticleDOI: 10.1152/PHYSREV.2001.81.2.741
Dennis J. Selkoe1Institutions (1)
Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

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Topics: Presenilin (64%), APH-1 (56%), Amyloid precursor protein secretase (53%) ...read more

5,644 Citations



Open accessJournal ArticleDOI: 10.1152/PHYSREV.00044.2005
Karen Bedard1, Karl-Heinz KrauseInstitutions (1)
Abstract: For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

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Topics: NADPH Oxidase 1 (67%), NOX4 (64%), NOX1 (63%) ...read more

5,183 Citations


Open accessJournal ArticleDOI: 10.1152/PHYSREV.00029.2006
Abstract: 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.

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Topics: Peroxynitrite (65%), Peroxynitrous acid (53%), Nitric oxide (51%)

4,938 Citations


Performance
Metrics
No. of papers from the Journal in previous years
YearPapers
202210
202152
202045
201939
201855
201738

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Journal's top 5 most impactful authors

Sadis Matalon

4 papers, 231 citations

Willis K. Samson

3 papers, 1 citations

Gerald I. Shulman

3 papers, 1.5K citations

Maria T. E. Hopman

2 papers, 310 citations

Michael Forgac

2 papers, 735 citations

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