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Hydrogen sulfide, the new kid on the block in redox signaling
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H. Bo et al. / Free Radical Biology and Medicine 96 (2016) S4–S14
However for the future it will be crucial to develop CNS-permeant NOX inhibitors. Such NOX inhibitors should either be isoformspecific (e.g. NOX2 for neurodegenerative disease and brain trauma) or act on a defined combination of NOX enzymes (e.g. NOX2/ NOX4 for stroke, or NOX1/NOX2 for Parkinson’s disease). Also, strategies to enrich therapeutic NOX inhibitors in the CNS should be investigated to allow action in the brain without necessarily inhibiting NOX in peripheral organs. Note also that the emerging concept of the importance of NOX2 in neuroregeneration might limit the use NOX2 inhibitors in neurodegenerative disease.
(OTKA; grant No.: K 109843), COST actions BM 1005 and BM 1203 and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences are greatly acknowledged. http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.046 PL-13
Role of reactive oxygen species (ROS) in degeneration of ageing muscle
http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.045 Aphrodite Vasilaki, Anne McArdle, Malcolm Jackson PL-12
Hydrogen sulfide, the new kid on the block in redox signaling Péter Nagy Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, Hungary
Hydrogen sulfide is a pivotal endogenous regulator of fundamental physiological functions. Under or overproduction of sulfide is associated with many pathophysiological events and hence sulfide biology is in the focus of drug development at present. However, owing to the promiscuous reactivity of sulfide with biomolecules, an increasing number of controversial observations appear in the literature, posing serious challenges to pharmacological endeavors. Our work is dedicated to reconcile these controversies by dissecting the underlying molecular mechanisms of sulfide's biological actions.1 The signal transduction mediatory roles of sulfide are associated with three chemically distinct models: 1) Persulfide formation of functional or regulatory Cys residues on peptides and proteins, 2) "cross-talk" with NO signaling pathways and 3) interactions with transition metal centers of metalloproteins. I will provide an overview of our contributions to these mechanisms. More specifically: 1) The formation of persulfides via non-enzymatic redox reactions driven pathways2 and their reductions by the thioredoxin and glutathione systems,3 2) the chemical foundations for the cooperative interactions of NO and H2S4 and 3) the reactions of sulfide with myeloperoxidase5 and hemoglobin derived redox intermediate species will be discussed with a rigorous chemical perspective. References: [1] Nagy P. Mechanistic chemical perspective of hydrogen sulfide signaling. Methods Enzymol. 2015;554:3-29. [2] Vasas A. et al. Kinetic and thermodynamic studies on the disulfide-bond reducing potential of hydrogen sulfide. Nitric oxide 2015;46:93-101. [3] Doka E. et al. A novel persulfide detection method reveals protein persulfide- and polysulfide-reducing functions of thioredoxin and glutathione systems. Sci Adv. 2016;2(1):e1500968. [4] Cortese-Krott MM. et al. Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl. Proc Natl Acad Sci USA. 2015 Aug 25;112(34):E4651-60. [5] Pálinkás, Z. et. al. Interactions of hydrogen sulfide with myeloperoxidase. Br. J. Pharmacol. 2014, 172, 1516-1532. Acknowledgement: Financial supports from FP7-PEOPLE-2010-RG (Marie Curie International Reintegration Grant; grant No.: PIRG08GA-2010-277006), The Hungarian National Science Foundation
Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
A significant loss of skeletal muscle mass with age is a major factor in frailty of the elderly. In addition to the loss of muscle mass, the remaining muscle is weaker, more susceptible to damage and recovers poorly from damage. This reduction in muscle mass and strength can have a major impact in the quality of life of older individuals. The hypothesis that a chronic increase in the generation of reactive oxygen species (ROS) plays a key role in the inability to respond to stress and that this is related to development of age-related muscle dysfunction has received considerable attention. Muscle generates superoxide and nitric oxide (NO) with the secondary formation of peroxynitrite, hydrogen peroxide and other ROS. Muscle has a substantial protective system and can enhance this system by increasing the production of cytoprotective proteins such as Heat Shock Proteins (HSPs) and antioxidant defence enzymes. ROS activities in many tissues increase with age and there is evidence that increased ROS generation may be the underlying reason for several age-related pathologies. During ageing, there is an accumulation of oxidative damage in muscle and interventions that maintain adaptive responses prevent the accumulation of oxidative damage and preserve some aspects of age-related muscle dysfunction. A clear link between age-related muscle loss and modified ROS production has been indicated by studies of mice lacking copper, zinc superoxide dismutase (CuZnSOD; Sod1-/- mice), which results in an increased cytosolic superoxide activity. These mice have an accelerated decline in muscle mass and function. Work from our laboratory has provided evidence of similar accumulation of oxidative damage in skeletal muscle of old wild-type mice and adult mice lacking CuZnSOD. Our findings support the hypothesis that increased generation of ROS is an important component of the ageing process, providing a link between accumulation of oxidative damage and muscle dysfunction. The authors would like to thank National Institutes of Health and Research into Ageing/ Age UK for funding. http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.047 PL-14
The cellular sources and targets of reactive oxygen species in Parkinson’s disease Andrey Y. Abramov Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK
H. Bo et al. / Free Radical Biology and Medicine 96 (2016) S4–S14
However for the future it will be crucial to develop CNS-permeant NOX inhibitors. Such NOX inhibitors should either be isoformspecific (e.g. NOX2 for neurodegenerative disease and brain trauma) or act on a defined combination of NOX enzymes (e.g. NOX2/ NOX4 for stroke, or NOX1/NOX2 for Parkinson’s disease). Also, strategies to enrich therapeutic NOX inhibitors in the CNS should be investigated to allow action in the brain without necessarily inhibiting NOX in peripheral organs. Note also that the emerging concept of the importance of NOX2 in neuroregeneration might limit the use NOX2 inhibitors in neurodegenerative disease.
(OTKA; grant No.: K 109843), COST actions BM 1005 and BM 1203 and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences are greatly acknowledged. http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.046 PL-13
Role of reactive oxygen species (ROS) in degeneration of ageing muscle
http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.045 Aphrodite Vasilaki, Anne McArdle, Malcolm Jackson PL-12
Hydrogen sulfide, the new kid on the block in redox signaling Péter Nagy Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, Hungary
Hydrogen sulfide is a pivotal endogenous regulator of fundamental physiological functions. Under or overproduction of sulfide is associated with many pathophysiological events and hence sulfide biology is in the focus of drug development at present. However, owing to the promiscuous reactivity of sulfide with biomolecules, an increasing number of controversial observations appear in the literature, posing serious challenges to pharmacological endeavors. Our work is dedicated to reconcile these controversies by dissecting the underlying molecular mechanisms of sulfide's biological actions.1 The signal transduction mediatory roles of sulfide are associated with three chemically distinct models: 1) Persulfide formation of functional or regulatory Cys residues on peptides and proteins, 2) "cross-talk" with NO signaling pathways and 3) interactions with transition metal centers of metalloproteins. I will provide an overview of our contributions to these mechanisms. More specifically: 1) The formation of persulfides via non-enzymatic redox reactions driven pathways2 and their reductions by the thioredoxin and glutathione systems,3 2) the chemical foundations for the cooperative interactions of NO and H2S4 and 3) the reactions of sulfide with myeloperoxidase5 and hemoglobin derived redox intermediate species will be discussed with a rigorous chemical perspective. References: [1] Nagy P. Mechanistic chemical perspective of hydrogen sulfide signaling. Methods Enzymol. 2015;554:3-29. [2] Vasas A. et al. Kinetic and thermodynamic studies on the disulfide-bond reducing potential of hydrogen sulfide. Nitric oxide 2015;46:93-101. [3] Doka E. et al. A novel persulfide detection method reveals protein persulfide- and polysulfide-reducing functions of thioredoxin and glutathione systems. Sci Adv. 2016;2(1):e1500968. [4] Cortese-Krott MM. et al. Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl. Proc Natl Acad Sci USA. 2015 Aug 25;112(34):E4651-60. [5] Pálinkás, Z. et. al. Interactions of hydrogen sulfide with myeloperoxidase. Br. J. Pharmacol. 2014, 172, 1516-1532. Acknowledgement: Financial supports from FP7-PEOPLE-2010-RG (Marie Curie International Reintegration Grant; grant No.: PIRG08GA-2010-277006), The Hungarian National Science Foundation
Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
A significant loss of skeletal muscle mass with age is a major factor in frailty of the elderly. In addition to the loss of muscle mass, the remaining muscle is weaker, more susceptible to damage and recovers poorly from damage. This reduction in muscle mass and strength can have a major impact in the quality of life of older individuals. The hypothesis that a chronic increase in the generation of reactive oxygen species (ROS) plays a key role in the inability to respond to stress and that this is related to development of age-related muscle dysfunction has received considerable attention. Muscle generates superoxide and nitric oxide (NO) with the secondary formation of peroxynitrite, hydrogen peroxide and other ROS. Muscle has a substantial protective system and can enhance this system by increasing the production of cytoprotective proteins such as Heat Shock Proteins (HSPs) and antioxidant defence enzymes. ROS activities in many tissues increase with age and there is evidence that increased ROS generation may be the underlying reason for several age-related pathologies. During ageing, there is an accumulation of oxidative damage in muscle and interventions that maintain adaptive responses prevent the accumulation of oxidative damage and preserve some aspects of age-related muscle dysfunction. A clear link between age-related muscle loss and modified ROS production has been indicated by studies of mice lacking copper, zinc superoxide dismutase (CuZnSOD; Sod1-/- mice), which results in an increased cytosolic superoxide activity. These mice have an accelerated decline in muscle mass and function. Work from our laboratory has provided evidence of similar accumulation of oxidative damage in skeletal muscle of old wild-type mice and adult mice lacking CuZnSOD. Our findings support the hypothesis that increased generation of ROS is an important component of the ageing process, providing a link between accumulation of oxidative damage and muscle dysfunction. The authors would like to thank National Institutes of Health and Research into Ageing/ Age UK for funding. http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.047 PL-14
The cellular sources and targets of reactive oxygen species in Parkinson’s disease Andrey Y. Abramov Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK