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Blanco MB, Greene LK, Welser KH, Ehmke EE, Yoder AD, Klopfer PH. Primate hibernation: The past, present, and promise of captive dwarf lemurs. Ann N Y Acad Sci 2024; 1540:178-190. [PMID: 39137248 DOI: 10.1111/nyas.15206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
The dwarf lemurs (Cheirogaleus spp.) of Madagascar are the only obligate hibernators among primates. Despite century-old field accounts of seasonal lethargy, and more recent evidence of hibernation in the western fat-tailed dwarf lemur (Cheirogaleus medius), inducing hibernation in captivity remained elusive for decades. This included the Duke Lemur Center (DLC), which maintains fat-tailed dwarf lemurs and has produced sporadic research on reproduction and metabolism. With cumulative knowledge from the field, a newly robust colony, and better infrastructure, we recently induced hibernation in DLC dwarf lemurs. We describe two follow-up experiments in subsequent years. First, we show that dwarf lemurs under stable cold conditions (13°C) with available food continued to eat daily, expressed shallower and shorter torpor bouts, and had a modified gut microbiome compared to peers without food. Second, we demonstrate that dwarf lemurs under fluctuating temperatures (12-30°C) can passively rewarm daily, which was associated with altered patterns of fat depletion and reduced oxidative stress. Despite the limitations of working with endangered primates, we highlight the promise of studying hibernation in captive dwarf lemurs. Follow-up studies on genomics and epigenetics, metabolism, and endocrinology could have relevance across multidisciplinary fields, from biomedicine to evolutionary biology, and conservation.
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Affiliation(s)
- Marina B Blanco
- Department of Biology, Duke University, Durham, North Carolina, USA
- Duke Lemur Center, Duke University, Durham, North Carolina, USA
| | - Lydia K Greene
- Department of Biology, Duke University, Durham, North Carolina, USA
- Duke Lemur Center, Duke University, Durham, North Carolina, USA
| | - Kay H Welser
- Duke Lemur Center, Duke University, Durham, North Carolina, USA
| | - Erin E Ehmke
- Duke Lemur Center, Duke University, Durham, North Carolina, USA
| | - Anne D Yoder
- Department of Biology, Duke University, Durham, North Carolina, USA
| | - Peter H Klopfer
- Department of Biology, Duke University, Durham, North Carolina, USA
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2
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Helena-Bueno K, Chan LI, Melnikov SV. Rippling life on a dormant planet: hibernation of ribosomes, RNA polymerases, and other essential enzymes. Front Microbiol 2024; 15:1386179. [PMID: 38770025 PMCID: PMC11102965 DOI: 10.3389/fmicb.2024.1386179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/21/2024] [Indexed: 05/22/2024] Open
Abstract
Throughout the tree of life, cells and organisms enter states of dormancy or hibernation as a key feature of their biology: from a bacterium arresting its growth in response to starvation, to a plant seed anticipating placement in fertile ground, to a human oocyte poised for fertilization to create a new life. Recent research shows that when cells hibernate, many of their essential enzymes hibernate too: they disengage from their substrates and associate with a specialized group of proteins known as hibernation factors. Here, we summarize how hibernation factors protect essential cellular enzymes from undesired activity or irreparable damage in hibernating cells. We show how molecular hibernation, once viewed as rare and exclusive to certain molecules like ribosomes, is in fact a widespread property of biological molecules that is required for the sustained persistence of life on Earth.
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Affiliation(s)
| | | | - Sergey V. Melnikov
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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3
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Nogueira-de-Sá PG, Bicudo JEPW, Chaui-Berlinck JG. Energy and time optimization during exit from torpor in vertebrate endotherms. J Comp Physiol B 2023:10.1007/s00360-023-01494-5. [PMID: 37171656 DOI: 10.1007/s00360-023-01494-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 04/25/2023] [Indexed: 05/13/2023]
Abstract
Torpor is used in small sized birds and mammals as an energy conservation trait. Considerable effort has been put towards elucidating the mechanisms underlying its entry and maintenance, but little attention has been paid regarding the exit. Firstly, we demonstrate that the arousal phase has a stereotyped dynamic: there is a sharp increase in metabolic rate followed by an increase in body temperature and, then, a damped oscillation in body temperature and metabolism. Moreover, the metabolic peak is around two-fold greater than the corresponding euthermic resting metabolic rate. We then hypothesized that either time or energy could be crucial variables to this event and constructed a model from a collection of first principles of physiology, control engineering and thermodynamics. From the model, we show that the stereotyped pattern of the arousal is a solution to save both time and energy. We extended the analysis to the scaling of the use of torpor by endotherms and show that variables related to the control system of body temperature emerge as relevant to the arousal dynamics. In this sense, the stereotyped dynamics of the arousal phase necessitates a certain profile of these variables which is not maintained as body size increases.
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Affiliation(s)
- Pedro Goes Nogueira-de-Sá
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brasil
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4
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A thermodynamic-based approach to model the entry into metabolic depression by mammals and birds. J Comp Physiol B 2022; 192:593-610. [PMID: 35737097 DOI: 10.1007/s00360-022-01442-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/05/2022] [Accepted: 05/15/2022] [Indexed: 10/17/2022]
Abstract
For decades, there was an intense debate in relation to the mechanism behind the entry into metabolic depression (EMD) of mammals and birds. The fulcrum of the argument was whether the depression of metabolic rate ([Formula: see text]) was caused by the drop in body temperature, the so-called "Q10 effect", or whether it was caused by a metabolic downregulation. One present-day model of this process is a qualitative (textual) description: the initial step of EDM would be a downregulation in [Formula: see text] from the value maintaining euthermia at a given ambient temperature to the basal metabolic rate of the animal and, then, Q10 effect would take over and drop [Formula: see text] to its lower levels. Despite widely accepted, this qualitative description still misses a theoretical analysis. Here, we transpose the descriptive model to a formal quantitative one and analyze it under necessary thermodynamic conditions of a system. We, then, compare the results of the formal model to empirical data of EMD by mammals and birds. The comparisons indicate that the metabolic evolution in the course of the entry phase does not follow the descriptive model. Instead, as proposed by alternate models, EMD is a downregulated process as a whole until a new equilibrium Tb is attained.
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Ambler M, Hitrec T, Pickering A. Turn it off and on again: characteristics and control of torpor. Wellcome Open Res 2022; 6:313. [PMID: 35087956 PMCID: PMC8764563 DOI: 10.12688/wellcomeopenres.17379.2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2022] [Indexed: 11/20/2022] Open
Abstract
Torpor is a hypothermic, hypoactive, hypometabolic state entered into by a wide range of animals in response to environmental challenge. This review summarises the current understanding of torpor. We start by describing the characteristics of the wide-ranging physiological adaptations associated with torpor. Next follows a discussion of thermoregulation, control of food intake and energy expenditure, and the interactions of sleep and thermoregulation, with particular emphasis on how those processes pertain to torpor. We move on to review the evidence for the systems that control torpor entry, including both the efferent circulating factors that signal the need for torpor, and the central processes that orchestrate it. Finally, we consider how the putative circuits responsible for torpor induction integrate with the established understanding of thermoregulation under non-torpid conditions and highlight important areas of uncertainty for future studies.
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Affiliation(s)
- Michael Ambler
- School of Physiology, Pharmacology, & Neuroscience, University of Bristol, Bristol, Bristol, BS8 1TD, UK
| | - Timna Hitrec
- School of Physiology, Pharmacology, & Neuroscience, University of Bristol, Bristol, Bristol, BS8 1TD, UK
| | - Anthony Pickering
- School of Physiology, Pharmacology, & Neuroscience, University of Bristol, Bristol, Bristol, BS8 1TD, UK
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6
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Sgarbi G, Hitrec T, Amici R, Baracca A, Di Cristoforo A, Liuzzi F, Luppi M, Solaini G, Squarcio F, Zamboni G, Cerri M. Mitochondrial respiration in rats during hypothermia resulting from central drug administration. J Comp Physiol B 2022; 192:349-360. [PMID: 35001173 DOI: 10.1007/s00360-021-01421-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 11/11/2021] [Accepted: 11/22/2021] [Indexed: 11/24/2022]
Abstract
The ability to induce a hypothermia resembling that of natural torpor would be greatly beneficial in medical and non-medical fields. At present, two procedures based on central nervous pharmacological manipulation have been shown to be effective in bringing core body temperature well below 30 °C in the rat, a non-hibernator: the first, based on the inhibition of a key relay in the central thermoregulatory pathway, the other, based on the activation of central adenosine A1 receptors. Although the role of mitochondria in the activation and maintenance of torpor has been extensively studied, no data are available for centrally induced hypothermia in non-hibernators. Thus, in the present work the respiration rate of mitochondria in the liver and in the kidney of rats following the aforementioned hypothermia-inducing treatments was studied. Moreover, to have an internal control, the same parameters were assessed in a well-consolidated model, i.e., mice during fasting-induced torpor. Our results show that state 3 respiration rate, which significantly decreased in the liver of mice, was unchanged in rats. An increase of state 4 respiration rate was observed in both species, although it was not statistically significant in rats under central adenosine stimulation. Also, a significant decrease of the respiratory control ratio was detected in both species. Finally, no effects were detected in kidney mitochondria in both species. Overall, in these hypothermic conditions liver mitochondria of rats remained active and apparently ready to be re-activated to produce energy and warm up the cells. These findings can be interpreted as encouraging in view of the finalization of a translational approach to humans.
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Affiliation(s)
- Gianluca Sgarbi
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Piazza di Porta S. Donato, 2, 40126, Bologna, Italy
| | - Timna Hitrec
- Laboratory of Autonomic and Behavioral Physiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy
| | - Roberto Amici
- Laboratory of Autonomic and Behavioral Physiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy
| | - Alessandra Baracca
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Piazza di Porta S. Donato, 2, 40126, Bologna, Italy
| | - Alessia Di Cristoforo
- Laboratory of Autonomic and Behavioral Physiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy
| | - Francesca Liuzzi
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Piazza di Porta S. Donato, 2, 40126, Bologna, Italy
| | - Marco Luppi
- Laboratory of Autonomic and Behavioral Physiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy
| | - Giancarlo Solaini
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Piazza di Porta S. Donato, 2, 40126, Bologna, Italy
| | - Fabio Squarcio
- Laboratory of Autonomic and Behavioral Physiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy
| | - Giovanni Zamboni
- Laboratory of Autonomic and Behavioral Physiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy
| | - Matteo Cerri
- Laboratory of Autonomic and Behavioral Physiology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy.
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Ambler M, Hitrec T, Pickering A. Turn it off and on again: characteristics and control of torpor. Wellcome Open Res 2021; 6:313. [DOI: 10.12688/wellcomeopenres.17379.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2021] [Indexed: 11/20/2022] Open
Abstract
Torpor is a hypothermic, hypoactive, hypometabolic state entered into by a wide range of animals in response to environmental challenge. This review summarises the current understanding of torpor. We start by describing the characteristics of the wide-ranging physiological adaptations associated with torpor. Next follows a discussion of thermoregulation, control of food intake and energy expenditure, and the interactions of sleep and thermoregulation, with particular emphasis on how those processes pertain to torpor. We move on to take a critical view of the evidence for the systems that control torpor entry, including both the efferent circulating factors that signal the need for torpor, and the central processes that orchestrate it. Finally, we consider how the putative circuits responsible for torpor induction integrate with the established understanding of thermoregulation under non-torpid conditions and highlight important areas of uncertainty for future studies.
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8
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Cerri M, Hitrec T, Luppi M, Amici R. Be cool to be far: Exploiting hibernation for space exploration. Neurosci Biobehav Rev 2021; 128:218-232. [PMID: 34144115 DOI: 10.1016/j.neubiorev.2021.03.037] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 01/08/2023]
Abstract
In mammals, torpor/hibernation is a state that is characterized by an active reduction in metabolic rate followed by a progressive decrease in body temperature. Torpor was successfully mimicked in non-hibernators by inhibiting the activity of neurons within the brainstem region of the Raphe Pallidus, or by activating the adenosine A1 receptors in the brain. This state, called synthetic torpor, may be exploited for many medical applications, and for space exploration, providing many benefits for biological adaptation to the space environment, among which an enhanced protection from cosmic rays. As regards the use of synthetic torpor in space, to fully evaluate the degree of physiological advantage provided by this state, it is strongly advisable to move from Earth-based experiments to 'in the field' tests, possibly on board the International Space Station.
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Affiliation(s)
- Matteo Cerri
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum -University of Bologna, Piazza di Porta S.Donato, 2 40126, Bologna, Italy.
| | - Timna Hitrec
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum -University of Bologna, Piazza di Porta S.Donato, 2 40126, Bologna, Italy.
| | - Marco Luppi
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum -University of Bologna, Piazza di Porta S.Donato, 2 40126, Bologna, Italy.
| | - Roberto Amici
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum -University of Bologna, Piazza di Porta S.Donato, 2 40126, Bologna, Italy.
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9
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Matsuo T, Isosaka T, Tang L, Soga T, Kobayakawa R, Kobayakawa K. Artificial hibernation/life-protective state induced by thiazoline-related innate fear odors. Commun Biol 2021; 4:101. [PMID: 33483561 PMCID: PMC7822961 DOI: 10.1038/s42003-020-01629-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 12/22/2020] [Indexed: 12/16/2022] Open
Abstract
Innate fear intimately connects to the life preservation in crises, although this relationships is not fully understood. Here, we report that presentation of a supernormal innate fear inducer 2-methyl-2-thiazoline (2MT), but not learned fear stimuli, induced robust systemic hypothermia/hypometabolism and suppressed aerobic metabolism via phosphorylation of pyruvate dehydrogenase, thereby enabling long-term survival in a lethal hypoxic environment. These responses exerted potent therapeutic effects in cutaneous and cerebral ischemia/reperfusion injury models. In contrast to hibernation, 2MT stimulation accelerated glucose uptake in the brain and suppressed oxygen saturation in the blood. Whole-brain mapping and chemogenetic activation revealed that the sensory representation of 2MT orchestrates physiological responses via brain stem Sp5/NST to midbrain PBN pathway. 2MT, as a supernormal stimulus of innate fear, induced exaggerated, latent life-protective effects in mice. If this system is preserved in humans, it may be utilized to give rise to a new field: "sensory medicine."
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Affiliation(s)
- Tomohiko Matsuo
- Institute of Biomedical Science, Kansai Medical University, Osaka, 573-1010, Japan
| | - Tomoko Isosaka
- Institute of Biomedical Science, Kansai Medical University, Osaka, 573-1010, Japan
| | - Lijun Tang
- Institute of Biomedical Science, Kansai Medical University, Osaka, 573-1010, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0052, Japan
| | - Reiko Kobayakawa
- Institute of Biomedical Science, Kansai Medical University, Osaka, 573-1010, Japan.
| | - Ko Kobayakawa
- Institute of Biomedical Science, Kansai Medical University, Osaka, 573-1010, Japan.
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10
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Lee SW. A Copernican Approach to Brain Advancement: The Paradigm of Allostatic Orchestration. Front Hum Neurosci 2019; 13:129. [PMID: 31105539 PMCID: PMC6499026 DOI: 10.3389/fnhum.2019.00129] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 03/28/2019] [Indexed: 01/16/2023] Open
Abstract
There are two main paradigms for brain-related science, with different implications for brain-focused intervention or advancement. The paradigm of homeostasis (“stability through constancy,” Walter Cannon), originating from laboratory-based experimental physiology pioneered by Claude Bernard, shows that living systems tend to maintain system functionality in the direction of constancy (or similitude). The aim of physiology is to elucidate the factors that maintain homeostasis, and therapeutics aim to correct abnormal factor functions. The homeostasis paradigm does not formally recognize influences outside its controlled experimental frames and it is variable in its modeling of neural contributions. The paradigm of allostatic orchestration (PAO) extends the principle of allostasis (“stability through change”) as originally put forth by Peter Sterling. The PAO originates from an evolutionary perspective and recognizes that biological set points change in anticipation of changing environments. The brain is the organ of central command, orchestrating cross-system operations to support optimal behavior at the level of the whole organism. Alternative views of blood pressure regulation and posttraumatic stress disorder (PTSD) illustrate differences between the paradigms. For the PAO, complexities of top-down neural effects and environmental context are foundational (not to be “factored out”), and anticipatory regulation is the principle of their interface. The allostatic state represents the integrated totality of brain-body interactions. Health itself is an allostatic state of optimal anticipatory oscillation, hypothesized to relate to the state of criticality, a mathematical point of poise between phases, on the border between order and disorder (or the “edge of chaos”). Diseases are allostatic states of impaired anticipatory oscillations, demonstrated as rigidifications of set points across the brain and body (disease comorbidity). Conciliation of the paradigms is possible, with “reactive homeostasis” resolved as an illusion stemming from the anticipation of environmental monotony. Considerations are presented with respect to implications of the two paradigms for brain-focused intervention or advancement; the hypothesis that the state of criticality is a vehicle for evolutionary processes; concordance with a philosophy of freedom based on ethical individualism as well as self-creativity, non-obsolescence, empowerment, and citizenship; and concluding reflections on the science and ethics of the placebo, and the potential for virtuous cycles of brain-Anthropocene interactions.
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Affiliation(s)
- Sung W Lee
- Scholarly Projects Unit, Department of Academic Affairs, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States
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11
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Hibernation and Radioprotection: Gene Expression in the Liver and Testicle of Rats Irradiated under Synthetic Torpor. Int J Mol Sci 2019; 20:ijms20020352. [PMID: 30654467 PMCID: PMC6359347 DOI: 10.3390/ijms20020352] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/23/2018] [Accepted: 01/11/2019] [Indexed: 01/02/2023] Open
Abstract
Hibernation has been proposed as a tool for human space travel. In recent years, a procedure to induce a metabolic state known as “synthetic torpor” in non-hibernating mammals was successfully developed. Synthetic torpor may not only be an efficient method to spare resources and reduce psychological problems in long-term exploratory-class missions, but may also represent a countermeasure against cosmic rays. Here we show the preliminary results from an experiment in rats exposed to ionizing radiation in normothermic conditions or synthetic torpor. Animals were irradiated with 3 Gy X-rays and organs were collected 4 h after exposure. Histological analysis of liver and testicle showed a reduced toxicity in animals irradiated in torpor compared to controls irradiated at normal temperature and metabolic activity. The expression of ataxia telangiectasia mutated (ATM) in the liver was significantly downregulated in the group of animal in synthetic torpor. In the testicle, more genes involved in the DNA damage signaling were downregulated during synthetic torpor. These data show for the first time that synthetic torpor is a radioprotector in non-hibernators, similarly to natural torpor in hibernating animals. Synthetic torpor can be an effective strategy to protect humans during long term space exploration of the solar system.
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Ren C, Li S, Rajah G, Shao G, Lu G, Han R, Huang Q, Li H, Ding Y, Jin K, Ji X. Hypoxia, hibernation and Neuroprotection: An Experimental Study in Mice. Aging Dis 2018; 9:761-768. [PMID: 30090664 PMCID: PMC6065299 DOI: 10.14336/ad.2018.0702] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 07/02/2018] [Indexed: 11/01/2022] Open
Abstract
Hibernation is a unique physiological state that evolved to survive periods of food shortages. It is characterized by profound decreases in metabolic rate, body temperature and physiological functions. Studies have shown that animals in hibernation can resist neurological damage. Here, we aimed to study whether hypoxia can induce a hibernation-like state in a traditionally non-hibernating animal and whether it is neuroprotective. All procedures were conducted according to international guidelines on laboratory animal safety. Mice C57BL/6 (19-21g) were placed into a 125 mL jar with fresh air and the jar was sealed with a rubber plug. For each run, the tolerance limit was judged by the animals' appearance for "air hunger". The animal was removed from the jar as soon as its first gasping breath appeared and was moved to another fresh-air-containing jar of similar volume. This procedure was performed in four runs. The hypoxia exposure significantly decreased oxygen (O2) consumption, carbon dioxide (CO2) production, respiratory rate and heart rate. Meanwhile, rectal temperature reached a minimum of 12.7±2.56°C, which is lower than a wide range of ambient temperatures. The mimicked hibernation decreased the infarct size in a focal cerebral ischemia mouse model. Our findings suggest the possibility of inducing suspended animation-like hibernation states for medical applications post injury.
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Affiliation(s)
- Changhong Ren
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
- Center of Stroke, Beijing Institute for Brain Disorder, Beijing 100069, China
| | - Sijie Li
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
| | - Gary Rajah
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Guo Shao
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
| | - Guowei Lu
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
| | - Rongrong Han
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
| | - Qingjian Huang
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
| | - Haiyan Li
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
| | - Yuchuan Ding
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Kunlin Jin
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Xunming Ji
- Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing 100053, China
- Center of Stroke, Beijing Institute for Brain Disorder, Beijing 100069, China
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13
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Pharmacologically induced reversible hypometabolic state mitigates radiation induced lethality in mice. Sci Rep 2017; 7:14900. [PMID: 29097738 PMCID: PMC5668348 DOI: 10.1038/s41598-017-15002-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/19/2017] [Indexed: 02/08/2023] Open
Abstract
Therapeutic hypothermia has proven benefits in critical care of a number of diseased states, where inflammation and oxidative stress are the key players. Here, we report that adenosine monophosphate (AMP) triggered hypometabolic state (HMS), 1–3 hours after lethal total body irradiation (TBI) for a duration of 6 hours, rescue mice from radiation-induced lethality and this effect is mediated by the persistent hypothermia. Studies with caffeine and 6N-cyclohexyladenosine, a non-selective antagonist and a selective agonist of adenosine A1 receptor (A1AR) respectively, indicated the involvement of adenosine receptor (AR) signaling. Intracerebroventricular injection of AMP also suggested possible involvement of central activation of AR signaling. AMP, induced HMS in a strain and age independent fashion and did not affect the behavioural and reproductive capacities. AMP induced HMS, mitigated radiation-induced oxidative DNA damage and loss of HSPCs. The increase in IL-6 and IL-10 levels and a shift towards anti-inflammatory milieu during the first 3–4 hours seems to be responsible for the augmented survival of HSPCs. The syngeneic bone marrow transplantation (BMT) studies further supported the role of radiation-induced inflammation in loss of bone marrow cellularity after TBI. We also showed that the clinically plausible mild hypothermia effectively mitigates TBI induced lethality in mice.
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Dugbartey GJ, Hardenberg MC, Kok WF, Boerema AS, Carey HV, Staples JF, Henning RH, Bouma HR. Renal Mitochondrial Response to Low Temperature in Non-Hibernating and Hibernating Species. Antioxid Redox Signal 2017; 27:599-617. [PMID: 28322600 DOI: 10.1089/ars.2016.6705] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
SIGNIFICANCE Therapeutic hypothermia is commonly applied to limit ischemic injury in organ transplantation, during cardiac and brain surgery and after cardiopulmonary resuscitation. In these procedures, the kidneys are particularly at risk for ischemia/reperfusion injury (IRI), likely due to their high rate of metabolism. Although hypothermia mitigates ischemic kidney injury, it is not a panacea. Residual mitochondrial failure is believed to be a key event triggering loss of cellular homeostasis, and potentially cell death. Subsequent rewarming generates large amounts of reactive oxygen species that aggravate organ injury. Recent Advances: Hibernators are able to withstand periods of profoundly reduced metabolism and body temperature ("torpor"), interspersed by brief periods of rewarming ("arousal") without signs of organ injury. Specific adaptations allow maintenance of mitochondrial homeostasis, limit oxidative stress, and protect against cell death. These adaptations consist of active suppression of mitochondrial function and upregulation of anti-oxidant enzymes and anti-apoptotic pathways. CRITICAL ISSUES Unraveling the precise molecular mechanisms that allow hibernators to cycle through torpor and arousal without precipitating organ injury may translate into novel pharmacological approaches to limit IRI in patients. FUTURE DIRECTIONS Although the precise signaling routes involved in natural hibernation are not yet fully understood, torpor-like hypothermic states with increased resistance to ischemia/reperfusion can be induced pharmacologically by 5'-adenosine monophosphate (5'-AMP), adenosine, and hydrogen sulfide (H2S) in non-hibernators. In this review, we compare the molecular effects of hypothermia in non-hibernators with natural and pharmacologically induced torpor, to delineate how safe and reversible metabolic suppression may provide resistance to renal IRI. Antioxid. Redox Signal. 27, 599-617.
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Affiliation(s)
- George J Dugbartey
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands .,2 Division of Cardiology, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Maarten C Hardenberg
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
| | - Wendelinde F Kok
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
| | - Ate S Boerema
- 3 Groningen Institute for Evolutionary Life Sciences, University of Groningen , Groningen, the Netherlands .,4 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
| | - Hannah V Carey
- 5 Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin , Madison, Wisconsin
| | - James F Staples
- 6 Department of Biology, University of Western Ontario , London, Canada
| | - Robert H Henning
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
| | - Hjalmar R Bouma
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands .,7 Department of Internal Medicine, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
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15
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Griko YV, Rask JC, Raychev R. Advantage of Animal Models with Metabolic Flexibility for Space Research Beyond Low Earth Orbit. ACTA ACUST UNITED AC 2017. [DOI: 10.1089/space.2016.0024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Yuri V. Griko
- Space Biosciences Division, NASA-Ames Research Center, Moffett Field, California
| | - Jon C. Rask
- Space Biosciences Division, NASA-Ames Research Center, Moffett Field, California
- KBRwyle, Moffett Field, California
| | - Raycho Raychev
- Space Challenges Program, EnduroSat, Inc., Sofia, Bulgaria
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16
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Sisa C, Turroni S, Amici R, Brigidi P, Candela M, Cerri M. Potential role of the gut microbiota in synthetic torpor and therapeutic hypothermia. World J Gastroenterol 2017; 23:406-413. [PMID: 28210076 PMCID: PMC5291845 DOI: 10.3748/wjg.v23.i3.406] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 11/18/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
Therapeutic hypothermia is today used in several clinical settings, among them the gut related diseases that are influenced by ischemia/reperfusion injury. This perspective paved the way to the study of hibernation physiology, in natural hibernators, highlighting an unexpected importance of the gut microbial ecosystem in hibernation and torpor. In natural hibernators, intestinal microbes adaptively reorganize their structural configuration during torpor, and maintain a mutualistic configuration regardless of long periods of fasting and cold temperatures. This allows the gut microbiome to provide the host with metabolites, which are essential to keep the host immunological and metabolic homeostasis during hibernation. The emerging role of the gut microbiota in the hibernation process suggests the importance of maintaining a mutualistic gut microbiota configuration in the application of therapeutic hypothermia as well as in the development of new strategy such as the use of synthetic torpor in humans. The possible utilization of tailored probiotics to mold the gut ecosystem during therapeutic hypothermia can also be taken into consideration as new therapeutic strategy.
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17
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Abstract
Autonomic thermoregulation is a recently acquired function, as it appears for the first time in mammals and provides the brain with the ability to control energy expenditure. The importance of such control can easily be highlighted by the ability of a heterogeneous group of mammals to actively reduce metabolic rate and enter a condition of regulated hypometabolism known as torpor. The central neural circuits of thermoregulatory cold defense have been recently unraveled and could in theory be exploited to reduce energy expenditure in species that do not normally use torpor, inducing a state called synthetic torpor. This approach may represent the first steps toward the development of a technology to induce a safe and reversible state of hypometabolism in humans, unlocking many applications ranging from new medical procedures to deep space travel.
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Affiliation(s)
- Matteo Cerri
- Department of Biomedical and Neuromotor Sciences, Physiology Division, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy;
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18
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Gemignani J, Gheysens T, Summerer L. Beyond astronaut's capabilities: The current state of the art. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2016; 2015:3615-8. [PMID: 26737075 DOI: 10.1109/embc.2015.7319175] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Space agencies have developed extensive expertise with sustaining human presence in low earth orbits and microgravity. Prolonged human presence in space beyond EarthâĂŹs orbit presents additional, some still unsolved issues. These are linked to the distance to Earth (impossibility of effective tele-operation, psychological effects linked to remoteness from Earth, required autonomy, the handling of emergencies, long mission durations), and to the environments beyond the Earth magnetosphere (radiation levels, local environments including atmospheres, dust, gravity, day-night cycles). These issues have impacts on the spacecraft design, the mission operations, astronaut selection and preparation and required supporting/ enabling technologies. This paper builds upon previous work by Rossini et al. , in critically reviewing and updating the current state of scientific research on enhancing astronaut's capabilities to face some of these challenges. In particular, it discusses the pertinence and feasibility of two approaches aiming at enhancing the chances of success of human missions: induced hibernation state and brain-machine interfaces.
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Induction of a Torpor-Like State by 5'-AMP Does Not Depend on H2S Production. PLoS One 2015; 10:e0136113. [PMID: 26295351 PMCID: PMC4546583 DOI: 10.1371/journal.pone.0136113] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 07/29/2015] [Indexed: 01/11/2023] Open
Abstract
Background Therapeutic hypothermia is used to reduce ischemia/reperfusion injury (IRI) during organ transplantation and major surgery, but does not fully prevent organ injury. Interestingly, hibernating animals undergo repetitive periods of low body temperature called ‘torpor’ without signs of organ injury. Recently, we identified an essential role of hydrogen sulfide (H2S) in entrance into torpor and preservation of kidney integrity during hibernation. A torpor-like state can be induced pharmacologically by injecting 5’-Adenosine monophosphate (5’-AMP). The mechanism by which 5’-AMP leads to the induction of a torpor-like state, and the role of H2S herein, remains to be unraveled. Therefore, we investigated whether induction of a torpor-like state by 5-AMP depends on H2S production. Methods To study the role of H2S on the induction of torpor, amino-oxyacetic acid (AOAA), a non-specific inhibitor of H2S, was administered before injection with 5'-AMP to block endogenous H2S production in Syrian hamster. To assess the role of H2S on maintenance of torpor induced by 5’-AMP, additional animals were injected with AOAA during torpor. Key Results During the torpor-like state induced by 5’-AMP, the expression of H2S- synthesizing enzymes in the kidneys and plasma levels of H2S were increased. Blockade of these enzymes inhibited the rise in the plasma level of H2S, but neither precluded torpor nor induced arousal. Remarkably, blockade of endogenous H2S production was associated with increased renal injury. Conclusions Induction of a torpor-like state by 5’-AMP does not depend on H2S, although production of H2S seems to attenuate renal injury. Unraveling the mechanisms by which 5’-AMP reduces the metabolism without organ injury may allow optimization of current strategies to limit (hypothermic) IRI and improve outcome following organ transplantation, major cardiac and brain surgery.
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20
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Decréau RA, Collman JP. Three toxic gases meet in the mitochondria. Front Physiol 2015; 6:210. [PMID: 26347655 PMCID: PMC4542460 DOI: 10.3389/fphys.2015.00210] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 07/13/2015] [Indexed: 12/14/2022] Open
Abstract
The rationale of the study was two-fold: (i) develop a functional synthetic model of the Cytochrome c oxidase (CcO) active site, (ii) use it as a convenient tool to understand or predict the outcome of the reaction of CcO with ligands (physiologically relevant gases and other ligands). At physiological pH and potential, the model catalyzes the 4-electron reduction of oxygen. This model was immobilized on self-assembled-monolayer (SAM) modified electrode. During catalytic oxygen reduction, electron delivery through SAMs is rate limiting, similar to the situation in CcO. This model contains all three redox-active components in CcO's active site, which are required to minimize the production of partially-reduced-oxygen-species (PROS): Fe-heme (“heme a3”) in a myoglobin-like model fitted with a proximal imidazole ligand, and a distal tris-imidazole Copper (“CuB”) complex, where one imidazole is cross-linked to a phenol (mimicking “Tyr244”). This functional CcO model demonstrates how CcO itself might tolerate the hormone NO (which diffuses through the mitochondria). It is proposed that CuB delivers superoxide to NO bound to Fe-heme forming peroxynitrite, then nitrate that diffuses away. Another toxic gas, H2S, has exceptional biological effects: at ~80 ppm, H2S induces a state similar to hibernation in mice, lowering the animal's temperature and slowing respiration. Using our functional CcO model, we have demonstrated that at the same concentration range H2S can reversibly inhibit catalytic oxygen reduction. Such a reversible catalytic process on the model was also demonstrated with an organic compound, tetrazole (TZ). Following studies showed that TZ reversibly inhibits respiration in isolated mitochondria, and induces deactivation of platelets, a mitochondria-rich key component of blood coagulation. Hence, this program is a rare example illustrating the use of a functional model to understand and predict physiologically important reactions at the active site of CcO.
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Affiliation(s)
- Richard A Decréau
- Department of Chemistry (ICMUB Institute), University of Burgundy Franche-Comté Dijon, France ; Department of Chemistry, Stanford University Stanford, CA, USA
| | - James P Collman
- Department of Chemistry, Stanford University Stanford, CA, USA
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21
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Lanaspa MA, Epperson LE, Li N, Cicerchi C, Garcia GE, Roncal-Jimenez CA, Trostel J, Jain S, Mant CT, Rivard CJ, Ishimoto T, Shimada M, Sanchez-Lozada LG, Nakagawa T, Jani A, Stenvinkel P, Martin SL, Johnson RJ. Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel. PLoS One 2015; 10:e0123509. [PMID: 25856396 PMCID: PMC4391924 DOI: 10.1371/journal.pone.0123509] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 03/04/2015] [Indexed: 12/14/2022] Open
Abstract
Hibernating animals develop fatty liver when active in summertime and undergo a switch to a fat oxidation state in the winter. We hypothesized that this switch might be determined by AMP and the dominance of opposing effects: metabolism through AMP deaminase (AMPD2) (summer) and activation of AMP-activated protein kinase (AMPK) (winter). Liver samples were obtained from 13-lined ground squirrels at different times during the year, including summer and multiples stages of winter hibernation, and fat synthesis and β-fatty acid oxidation were evaluated. Changes in fat metabolism were correlated with changes in AMPD2 activity and intrahepatic uric acid (downstream product of AMPD2), as well as changes in AMPK and intrahepatic β-hydroxybutyrate (a marker of fat oxidation). Hepatic fat accumulation occurred during the summer with relatively increased enzymes associated with fat synthesis (FAS, ACL and ACC) and decreased enoyl CoA hydratase (ECH1) and carnitine palmitoyltransferase 1A (CPT1A), rate limiting enzymes of fat oxidation. In summer, AMPD2 activity and intrahepatic uric acid levels were high and hepatic AMPK activity was low. In contrast, the active phosphorylated form of AMPK and β-hydroxybutyrate both increased during winter hibernation. Therefore, changes in AMPD2 and AMPK activity were paralleled with changes in fat synthesis and fat oxidation rates during the summer-winter cycle. These data illuminate the opposing forces of metabolism of AMP by AMPD2 and its availability to activate AMPK as a switch that governs fat metabolism in the liver of hibernating ground squirrel.
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Affiliation(s)
- Miguel A. Lanaspa
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
- * E-mail:
| | - L. Elaine Epperson
- Department of Cell and Developmental Biology, Aurora, CO, 80045, United States of America
| | - Nanxing Li
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Christina Cicerchi
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Gabriela E. Garcia
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Carlos A. Roncal-Jimenez
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Jessica Trostel
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Swati Jain
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Colin T. Mant
- Department of Biochemistry and Molecular Genetics, Aurora, CO, 80045, United States of America
| | - Christopher J. Rivard
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Takuji Ishimoto
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Michiko Shimada
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Laura Gabriela Sanchez-Lozada
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
- Laboratory of Renal Physiopathology and Nephrology Dept, INC Ignacio Chavez, Mexico City, Mexico
| | - Takahiko Nakagawa
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Alkesh Jani
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
| | - Peter Stenvinkel
- Division of Renal Medicine, Department of Clinical Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Sandra L. Martin
- Department of Cell and Developmental Biology, Aurora, CO, 80045, United States of America
| | - Richard J. Johnson
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, United States of America
- Division of Nephrology, Eastern Colorado Health System, Department of Veteran Affairs, Denver, CO, United States of America
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22
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RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature 2015; 518:236-9. [PMID: 25607368 PMCID: PMC4338605 DOI: 10.1038/nature14142] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 12/05/2014] [Indexed: 12/18/2022]
Abstract
In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity1. Reduction in synapse number is a consistent early feature of neurodegenerative diseases2, 3, suggesting deficient compensatory mechanisms. While much is known about toxic processes leading to synaptic dysfunction and loss in these disorders2,3, how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity4, 5. We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number cold-shock proteins in the brain, including the RNA binding protein, RBM36. The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5×FAD (Alzheimer-type) mice7, the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. Further, RBM3 over-expression, achieved either by boosting endogenous levels through hypothermia prior to the loss of the RBM3 response, or by lentiviral delivery, resulted in sustained synaptic protection in 5×FAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold shock pathways as potential protective therapies in neurodegenerative disorders.
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Tessier SN, Storey KB. To be or not to be: the regulation of mRNA fate as a survival strategy during mammalian hibernation. Cell Stress Chaperones 2014; 19:763-76. [PMID: 24789358 PMCID: PMC4389848 DOI: 10.1007/s12192-014-0512-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 04/13/2014] [Indexed: 12/20/2022] Open
Abstract
Mammalian hibernators undergo profound behavioral, physiological, and biochemical changes in order to cope with hypothermia, ischemia-reperfusion, and finite fuel reserves over days or weeks of continuous torpor. Against a backdrop of global reductions in energy-expensive processes such as transcription and translation, a subset of genes/proteins are strategically upregulated in order to meet challenges associated with hibernation. Consequently, hibernation involves substantial transcriptional and posttranscriptional regulatory mechanisms and provides a phenomenon with which to understand how a set of common genes/proteins can be differentially regulated in order to enhance stress tolerance beyond that which is possible for nonhibernators. The present review focuses on the involvement of messenger RNA (mRNA) interacting factors that play a role in the regulation of gene/protein expression programs that define the hibernating phenotype. These include proteins involved in mRNA processing (i.e., capping, splicing, and polyadenylation) and the possible role of alternative splicing as a means of enhancing protein diversity. Since the total pool of mRNA remains constant throughout torpor, mechanisms which enhance mRNA stability are discussed in the context of RNA binding proteins and mRNA decay pathways. Furthermore, mechanisms which control the global reduction of cap-dependent translation and the involvement of internal ribosome entry sites in mRNAs encoding stress response proteins are also discussed. Finally, the concept of regulating each of these factors in discrete subcellular compartments for enhanced efficiency is addressed. The analysis draws on recent research from several well-studied mammalian hibernators including ground squirrels, bats, and bears.
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Affiliation(s)
- Shannon N. Tessier
- Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6 Canada
| | - Kenneth B. Storey
- Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6 Canada
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Wang Y, Zhang A, Lu S, Pan X, Jia D, Yu W, Jiang Y, Li X, Wang X, Zhang J, Hou L, Sun Y. Adenosine 5'-monophosphate-induced hypothermia inhibits the activation of ERK1/2, JNK, p38 and NF-κB in endotoxemic rats. Int Immunopharmacol 2014; 23:205-10. [PMID: 25218163 DOI: 10.1016/j.intimp.2014.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 09/01/2014] [Accepted: 09/02/2014] [Indexed: 11/29/2022]
Abstract
Many studies have shown that LPS mainly activates four signal transduction pathways to induce inflammation, namely the p38, ERK1/2, JNK and IKK/NF-κB pathways. Studies have demonstrated that 5'-AMP-induced hypothermia (AIH) exhibits high anti-inflammatory capabilities. In this study, we explore that how AIH inhibits the inflammatory response. Wistar rats were divided into five groups: a control group, an LPS group, a 5'-AMP pre-treatment group, a 5'-AMP post-treatment group and a 5'-AMP group. For each group, plasma and lung were collected from the rats at 6h and 12h after LPS injection. ELISA assays were used to detect plasma levels of CD14, CRP and MCP-1. Inflammatory pathway activation and TLR4 expression were assayed separately by Western blot analysis and immunohistochemistry. Our results showed that rats treated with AIH either before or after an LPS-challenge had a significant decrease in plasma levels of CD14, CRP and TLR4 compared with rats that received LPS only. Western blot analysis showed that AIH inhibited the activation of extracellular signal-regulated kinases (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) and NF-κB in inflammatory rats. Our study concluded that AIH attenuated LPS-induced inflammation mainly by inhibiting activation on the ERK1/2, p38, JNK and NF-κB signaling pathways.
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Affiliation(s)
- Yunlong Wang
- Gout Laboratory, The Affiliated Hospital of Medical College Qingdao University, Shandong Provincial Key Laboratory of Metabolic Diseases, 16 Jiangsu Road, Qingdao, China
| | - Aihua Zhang
- Department of Biochemistry, Medical College, Qingdao University, Qingdao, Shandong, China
| | - Shulai Lu
- Stomatological Department, Qingdao Municipal Hospital, Qingdao, China
| | - Xinting Pan
- ICU, The Affiliated Hospital of Medical College, 16 Jiangsu Road, Qingdao, China
| | - Dongmei Jia
- Pathology Department, Qingdao Municipal Hospital, Qingdao, China
| | - Wenjuan Yu
- Pathology Department, The Affiliated Hospital of Medical College Qingdao University, China
| | - Yanxia Jiang
- Pathology Department, The Affiliated Hospital of Medical College Qingdao University, China
| | - Xinde Li
- Gout Laboratory, The Affiliated Hospital of Medical College Qingdao University, Shandong Provincial Key Laboratory of Metabolic Diseases, 16 Jiangsu Road, Qingdao, China
| | - Xuefeng Wang
- Gout Laboratory, The Affiliated Hospital of Medical College Qingdao University, Shandong Provincial Key Laboratory of Metabolic Diseases, 16 Jiangsu Road, Qingdao, China
| | - Jidong Zhang
- Department of Cardiology, The Affiliated Hospital of Medical College Qingdao University, 16 Jiangsu Road, Qingdao, China
| | - Lin Hou
- Department of Biochemistry, Medical College, Qingdao University, Qingdao, Shandong, China.
| | - Yunbo Sun
- ICU, The Affiliated Hospital of Medical College, 16 Jiangsu Road, Qingdao, China.
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Xu Y, Kim ER, Fan S, Xia Y, Xu Y, Huang C, Tong Q. Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists. Biochem Biophys Res Commun 2014; 451:184-9. [PMID: 25065745 DOI: 10.1016/j.bbrc.2014.07.079] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 07/17/2014] [Indexed: 01/05/2023]
Abstract
The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5'AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII's effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature.
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Affiliation(s)
- Yuanzhong Xu
- Brown Foundation Institute of Molecular Medicine, University of Texas Medical School at Houston, TX 77030, USA
| | - Eun Ran Kim
- Brown Foundation Institute of Molecular Medicine, University of Texas Medical School at Houston, TX 77030, USA
| | - Shengjie Fan
- Brown Foundation Institute of Molecular Medicine, University of Texas Medical School at Houston, TX 77030, USA; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Yan Xia
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yong Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Qingchun Tong
- Brown Foundation Institute of Molecular Medicine, University of Texas Medical School at Houston, TX 77030, USA; Programs in Neuroscience and Biochemistry, Graduate School of Biological Sciences, University of Texas Medical School at Houston, TX 77030, USA.
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Knapp J, Schneider A, Nees C, Bruckner T, Böttiger BW, Popp E. Effects of adenosine monophosphate on induction of therapeutic hypothermia and neuronal damage after cardiopulmonary resuscitation in rats. Resuscitation 2014; 85:1291-7. [PMID: 24978110 DOI: 10.1016/j.resuscitation.2014.05.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 05/16/2014] [Accepted: 05/29/2014] [Indexed: 11/16/2022]
Abstract
BACKGROUND Animal studies and pathophysiological considerations suggest that therapeutic hypothermia after cardiopulmonary resuscitation is the more effective the earlier it is induced. Therefore this study is sought to examine whether pharmacological facilitated hypothermia by administration of 5'-adenosine monophosphate (AMP) is neuroprotective in a rat model of cardiac arrest (CA) and resuscitation. METHODS Sixty-one rats were subjected to CA. After 6 min of ventricular fibrillation advanced cardiac life support was started. After successful return of spontaneous circulation (ROSC, n=40), animals were randomized either to placebo group (n=14) or AMP group (800 mg/kg body weight, n=14). Animals were kept at an ambient temperature of 18°C for 12 h after ROSC and core body temperature was measured using a telemetry temperature probe. Neuronal damage was analyzed by counting Nissl-positive (i.e. viable) neurons and TUNEL-positive (i.e. apoptotic) cells in coronal brain sections 7 days after ROSC. Functional status evaluated on days 1, 3 and 7 after ROSC by a tape removal test. RESULTS Time until core body temperature dropped to <34.0°C was 31 min [28; 45] in AMP-treated animals and 125 min [90; 180] in the control group (p=0.003). Survival until 7 days after ROSC was comparable in both groups. Also number of Nissl-positive cells (AMP: 1 [1; 7] vs. placebo: 2 [1; 3] per 100 pixel; p=0.66) and TUNEL-positive cells (AMP: 56 [44; 72] vs. placebo: 53 [41; 67] per 100 pixel; p=0.70) did not differ. Neither did AMP affect functional neurological outcome up to 7 days after ROSC. Mean arterial pressure 20 min after ROSC was 49 [45; 55] mmHg in the AMP group in comparison to 91 [83; 95] mmHg in the control group (p<0.001). CONCLUSION Although application of AMP reduced the time to reach a core body temperature of <34°C neither survival was improved nor neuronal damage attenuated. Reason for this is probably induction of marked hypotension as an adverse reaction to AMP treatment.
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Affiliation(s)
- Jürgen Knapp
- Department of Anaesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
| | - Andreas Schneider
- Department of Anaesthesiology and Postoperative Intensive Care Medicine, University of Cologne, Kerpener Str. 62, D-50937 Köln, Germany
| | - Corinna Nees
- Department of Anaesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany
| | - Thomas Bruckner
- Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany
| | - Bernd W Böttiger
- Department of Anaesthesiology and Postoperative Intensive Care Medicine, University of Cologne, Kerpener Str. 62, D-50937 Köln, Germany
| | - Erik Popp
- Department of Anaesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany
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Abstract
We have demonstrated that 5'-adenosine-monophosphate (5'-AMP) can be used to induce deep hypometabolism in mice and other non-hibernating mammals. This reversible 5'-AMP induced hypomatabolism (AIHM) allows mice to maintain a body temperature about 1°C above the ambient temperature for several hours before spontaneous reversal to euthermia. Our biochemical and gene expression studies suggested that the molecular processes involved in AIHM behavior most likely occur at the metabolic interconversion level, rather than the gene or protein expression level. To understand the metabolic processes involved in AIHM behavior, we conducted a non-targeted comparative metabolomics investigation at multiple stages of AIHM in the plasma, liver and brain of animals that underwent AIHM. Dozens of metabolites representing many important metabolic pathways were detected and measured using a metabolite profiling platform combining both LC-MS and GC-MS. Our findings indicate that there is a widespread suppression of energy generating metabolic pathways but lipid metabolism appears to be minimally altered. Regulation of carbohydrate metabolites appears to be the major way the animal utilizes energy in AIHM and during the following recovery process. The 5'-AMP administered has largely been catabolized by the time the animals have entered AIHM. During AIHM, the urea cycle appears to be functional, helping to avoid ammonia toxicity. Of all tissues studied, brain's metabolite flux is the least affected by AIHM.
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Affiliation(s)
- Zhaoyang Zhao
- Department of Biochemistry and Molecular Biology, Medical School, University of Texas, Health Science Center (UTHealth), Houston, Texas, USA
| | - Anita Van Oort
- Department of Biochemistry and Molecular Biology, Medical School, University of Texas, Health Science Center (UTHealth), Houston, Texas, USA
| | - Zhenyin Tao
- Department of Biochemistry and Molecular Biology, Medical School, University of Texas, Health Science Center (UTHealth), Houston, Texas, USA
| | - William G O'Brien
- Department of Biochemistry and Molecular Biology, Medical School, University of Texas, Health Science Center (UTHealth), Houston, Texas, USA
| | - Cheng Chi Lee
- Department of Biochemistry and Molecular Biology, Medical School, University of Texas, Health Science Center (UTHealth), Houston, Texas, USA
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Affiliation(s)
- K. H. Dausmann
- Department of Animal Ecology and Conservation, Biocentre Grindel; University of Hamburg; Hamburg Germany
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Bouma HR, Mandl JN, Strijkstra AM, Boerema AS, Kok JW, van Dam A, Ijzerman A, Kroese FGM, Henning RH. 5'-AMP impacts lymphocyte recirculation through activation of A2B receptors. J Leukoc Biol 2013; 94:89-98. [PMID: 23682128 PMCID: PMC3685012 DOI: 10.1189/jlb.1212613] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2012] [Revised: 04/08/2013] [Accepted: 04/17/2013] [Indexed: 01/17/2023] Open
Abstract
Natural hibernation consists of torpid phases with metabolic suppression alternating with euthermic periods. Induction of torpor holds substantial promise in various medical conditions, including trauma, major surgery, and transplantation. Torpor in mice can be induced pharmacologically by 5'-AMP. Previously, we showed that during natural torpor, the reduction in body temperature results in lymphopenia via a reduction in plasma S1P. Here, we show that during torpor induced by 5'-AMP, there is a similar reduction in the number of circulating lymphocytes that is a result of their retention in secondary lymphoid organs. This lymphopenia could be mimicked by engagement of A(2B)Rs by a selective A(2B)R agonist (LUF6210) in the absence of changes in temperature and prevented by A(2B)R antagonists during 5'-AMP-induced torpor. In addition, forced cooling of mice led to peripheral blood lymphopenia, independent of A(2B)R signaling. The induction of torpor using 5'-AMP impacted the migration of lymphocytes within and between secondary lymphoid organs. During torpor, the homing into LNs was impaired, and two-photon intravital microscopy revealed that cell motility was decreased significantly and rapidly upon 5'-AMP administration. Furthermore, the S1P plasma concentration was reduced by 5'-AMP but not by LUF6210. S1P plasma levels restored upon arousal. Likely, the reduced migration in LNs combined with the reduced S1P plasma level substantially reduces lymphocyte egress after injection of 5'-AMP. In conclusion, 5'-AMP induces a state of pharmacological torpor in mice, during which, lymphopenia is governed primarily by body temperature-independent suppression of lymphocyte egress from LNs.
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Affiliation(s)
- Hjalmar R Bouma
- University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
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In vivo molecular imaging of [125I]-labeled 3-iodothyronamine: A hibernation-inducing agent. Appl Radiat Isot 2013; 73:74-8. [DOI: 10.1016/j.apradiso.2012.11.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 11/20/2012] [Accepted: 11/29/2012] [Indexed: 11/17/2022]
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Hypothermia induced by adenosine 5'-monophosphate attenuates early stage injury in an acute gouty arthritis rat model. Rheumatol Int 2013; 33:2085-92. [PMID: 23408150 DOI: 10.1007/s00296-013-2676-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 01/15/2013] [Indexed: 12/17/2022]
Abstract
To investigate whether the hypothermia induced by Adenosine 5'-Monophosphate (5'-AMP) could attenuate early stage injury in a rat acute gouty arthritis model. Ankle joint injection with monosodium urate monohydrate crystals (MSU crystals) in hypothermia rat model which was induced by 5'-AMP and then observe whether hypothermia induced by 5'-AMP could be effectively inhibit the inflammation on acute gouty arthritis in rats. AMP-induced hypothermia has protective effects on our acute gouty arthritis, which was demonstrated by the following criteria: (1) a significant reduction in the ankle swelling (p < 0.001); (2) a significant decrease in the occurrence of leukocyte infiltration and mild hemorrhage; (3) a significant reduction in the presence of serum Interleukin-1β (IL-1β, p < 0.001) and metalloproteinase-9 (MMP-9, p < 0.001); and (4) a significant inhibition in the Nuclear Factor -κappaB (NF-κB) activity (p < 0.001). AMP-induced hypothermia could inhibit acute inflammation reaction and protect the synovial tissue against acute injury in a rat acute gouty arthritis model.
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Cerri M, Mastrotto M, Tupone D, Martelli D, Luppi M, Perez E, Zamboni G, Amici R. The inhibition of neurons in the central nervous pathways for thermoregulatory cold defense induces a suspended animation state in the rat. J Neurosci 2013; 33:2984-93. [PMID: 23407956 PMCID: PMC6619194 DOI: 10.1523/jneurosci.3596-12.2013] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 12/19/2012] [Accepted: 12/20/2012] [Indexed: 12/19/2022] Open
Abstract
The possibility of inducing a suspended animation state similar to natural torpor would be greatly beneficial in medical science, since it would avoid the adverse consequence of the powerful autonomic activation evoked by external cooling. Previous attempts to systemically inhibit metabolism were successful in mice, but practically ineffective in nonhibernators. Here we show that the selective pharmacological inhibition of key neurons in the central pathways for thermoregulatory cold defense is sufficient to induce a suspended animation state, resembling natural torpor, in a nonhibernator. In rats kept at an ambient temperature of 15°C and under continuous darkness, the prolonged inhibition (6 h) of the rostral ventromedial medulla, a key area of the central nervous pathways for thermoregulatory cold defense, by means of repeated microinjections (100 nl) of the GABA(A) agonist muscimol (1 mm), induced the following: (1) a massive cutaneous vasodilation; (2) drastic drops in deep brain temperature (reaching a nadir of 22.44 ± 0.74°C), heart rate (from 440 ± 13 to 207 ± 12 bpm), and electroencephalography (EEG) power; (3) a modest decrease in mean arterial pressure; and (4) a progressive shift of the EEG power spectrum toward slow frequencies. After the hypothermic bout, all animals showed a massive increase in NREM sleep Delta power, similarly to that occurring in natural torpor. No behavioral abnormalities were observed in the days following the treatment. Our results strengthen the potential role of the CNS in the induction of hibernation/torpor, since CNS-driven changes in organ physiology have been shown to be sufficient to induce and maintain a suspended animation state.
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Affiliation(s)
- Matteo Cerri
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum-University of Bologna, 40126 Bologna Italy.
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Muzzi M, Blasi F, Chiarugi A. AMP-dependent hypothermia affords protection from ischemic brain injury. J Cereb Blood Flow Metab 2013; 33:171-4. [PMID: 23211965 PMCID: PMC3564206 DOI: 10.1038/jcbfm.2012.181] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
In light of the relevance of therapeutic hypothermia to stroke treatment, we investigated whether 5'-adenosine monophosphate (AMP)-dependent cooling affords protection from ischemic brain injury. We show that hypothermia by AMP is because of adenosine A1 receptor (A1R) activation and is not invariantly associated with hypotension. Inhibition of ecto-5'-nucleotidase-dependent constitutive degradation of brain extracellular AMP by methylene-ADP (AMPCP) also suffices to prompt A1R-dependent hypothermia without hypotension. Both intraischemic and postischemic hypothermia by AMP or AMPCP reduce infarct volumes and mortality of mice subjected to transient middle cerebral artery occlusion. Data disclose that AMP-dependent hypothermia is of therapeutic relevance to treatment of brain ischemia.
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Affiliation(s)
- Mirko Muzzi
- Department of Preclinical and Clinical Pharmacology University of Florence, Florence, Italy.
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Neurological basis of AMP-dependent thermoregulation and its relevance to central and peripheral hyperthermia. J Cereb Blood Flow Metab 2013; 33:183-90. [PMID: 23093068 PMCID: PMC3564191 DOI: 10.1038/jcbfm.2012.157] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Therapeutic hypothermia is of relevance to treatment of increased body temperature and brain injury, but drugs inducing selective, rapid, and safe cooling in humans are not available. Here, we show that injections of adenosine 5'-monophosphate (AMP), an endogenous nucleotide, promptly triggers hypothermia in mice by directly activating adenosine A1 receptors (A1R) within the preoptic area (POA) of the hypothalamus. Inhibition of constitutive degradation of brain extracellular AMP by targeting ecto 5'-nucleotidase, also suffices to prompt hypothermia in rodents. Accordingly, sensitivity of mice and rats to the hypothermic effect of AMP is inversely related to their hypothalamic 5'-nucleotidase activity. Single-cell electrophysiological recording indicates that AMP reduces spontaneous firing activity of temperature-insensitive neurons of the mouse POA, thereby retuning the hypothalamic thermoregulatory set point towards lower temperatures. Adenosine 5'-monophosphate also suppresses prostaglandin E2-induced fever in mice, having no effects on peripheral hyperthermia triggered by dioxymetamphetamine (ecstasy) overdose. Together, data disclose the role of AMP, 5'-nucleotidase, and A1R in hypothalamic thermoregulation, as well and their therapeutic relevance to treatment of febrile illness.
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ATP induces mild hypothermia in rats but has a strikingly detrimental impact on focal cerebral ischemia. J Cereb Blood Flow Metab 2013; 33:jcbfm2012146. [PMID: 23072747 PMCID: PMC3597371 DOI: 10.1038/jcbfm.2012.146] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Ischemic stroke is a devastating condition lacking effective therapies. A promising approach to attenuate ischemic injury is mild hypothermia. Recent studies show that adenosine nucleotides can induce hypothermia in mice. The purpose of the present study was to test the hypothesis that adenosine 5'-triphosphate (ATP) induces mild hypothermia in rats and reduces ischemic brain injury. We found that intraperitoneal injections of ATP decreased core body temperature in a dose-dependent manner; the dose appropriate for mild hypothermia was 2 g/kg. When ATP-induced hypothermia was applied to stroke induced by middle cerebral artery occlusion, however, a neuroprotective effect was not observed. Instead, the infarct volume grew even larger in ATP-treated rats. This was accompanied by an increased rate of seizure events, hemorrhagic transformation, and higher mortality. Continuous monitoring of physiologic parameters revealed that ATP reduced heartbeat rate and blood pressure. ATP also increased blood glucose, accompanied by severe acidosis and hypocalcemia. Western blotting showed that ATP decreased levels of both phospho-Akt and total-Akt in the cortex. Our results reveal that, despite inducing hypothermia, ATP is not appropriate for protecting the brain against stroke. Instead, we show for the first time that ATP treatment is associated with exaggerated ischemic outcomes and dangerous systemic side effects.
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Hypothermia induced by adenosine 5'-monophosphate attenuates acute lung injury induced by LPS in rats. Mediators Inflamm 2012; 2012:459617. [PMID: 23024464 PMCID: PMC3449152 DOI: 10.1155/2012/459617] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 07/18/2012] [Accepted: 08/02/2012] [Indexed: 11/18/2022] Open
Abstract
We have built a rat's model to investigate whether the hypothermia induced by adenosine 5′-monophosphate (5′-AMP) (AIH) could attenuate acute lung injury induced by LPS in rats. We detected the inflammatory cytokine levels in the plasma and bronchoalveolar lavage fluid samples, and we analyzed the pathological changes in the lungs. We have found that AIH can effectively inhibit acute inflammatory reactions and protect the lung from acute injury induced by LPS in rats.
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Stein A, Mao Z, Morrison JP, Fanucchi MV, Postlethwait EM, Patel RP, Kraus DW, Doeller JE, Bailey SM. Metabolic and cardiac signaling effects of inhaled hydrogen sulfide and low oxygen in male rats. J Appl Physiol (1985) 2012; 112:1659-69. [PMID: 22403348 DOI: 10.1152/japplphysiol.01598.2011] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Low concentrations of inhaled hydrogen sulfide (H(2)S) induce hypometabolism in mice. Biological effects of H(2)S in in vitro systems are augmented by lowering O(2) tension. Based on this, we hypothesized that reduced O(2) tension would increase H(2)S-mediated hypometabolism in vivo. To test this, male Sprague-Dawley rats were exposed to 80 ppm H(2)S at 21% O(2) or 10.5% O(2) for 6 h followed by 1 h recovery at room air. Rats exposed to H(2)S in 10.5% O(2) had significantly decreased body temperature and respiration compared with preexposure levels. Heart rate was decreased by H(2)S administered under both O(2) levels and did not return to preexposure levels after 1 h recovery. Inhaled H(2)S caused epithelial exfoliation in the lungs and increased plasma creatine kinase-MB activity. The effect of inhaled H(2)S on prosurvival signaling was also measured in heart and liver. H(2)S in 21% O(2) increased Akt-P(Ser473) and GSK-3β-P(Ser9) in the heart whereas phosphorylation was decreased by H(2)S in 10.5% O(2), indicating O(2) dependence in regulating cardiac signaling pathways. Inhaled H(2)S and low O(2) had no effect on liver Akt. In summary, we found that lower O(2) was needed for H(2)S-dependent hypometabolism in rats compared with previous findings in mice. This highlights the possibility of species differences in physiological responses to H(2)S. Inhaled H(2)S exposure also caused tissue injury to the lung and heart, which raises concerns about the therapeutic safety of inhaled H(2)S. In conclusion, these findings demonstrate the importance of O(2) in influencing physiological and signaling effects of H(2)S in mammalian systems.
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Affiliation(s)
- Asaf Stein
- Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
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Bouma HR, Verhaag EM, Otis JP, Heldmaier G, Swoap SJ, Strijkstra AM, Henning RH, Carey HV. Induction of torpor: mimicking natural metabolic suppression for biomedical applications. J Cell Physiol 2012; 227:1285-90. [PMID: 21618525 DOI: 10.1002/jcp.22850] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mammalian hibernation consists of periods of depressed metabolism and reduced body temperature called "torpor" that are interspersed by normothermic arousal periods. Numerous cellular processes are halted during torpor, including transcription, translation, and ion homeostasis. Hibernators are able to survive long periods of low blood flow and body temperature followed by rewarming and reperfusion without overt signs of organ injury, which makes these animals excellent models for application of natural protective mechanisms to human medicine. This review examines efforts to induce torpor-like states in non-hibernating species using pharmacological compounds. Elucidating the underlying mechanisms of natural and pharmacologically induced torpor will speed the development of new clinical approaches to treat a variety of trauma and stress states in humans.
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Affiliation(s)
- Hjalmar R Bouma
- Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Renal protection from prolonged cold ischemia and warm reperfusion in hibernating squirrels. Transplantation 2012; 92:1215-21. [PMID: 22082817 DOI: 10.1097/tp.0b013e3182366401] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND We have previously shown that cold ischemia (CI) results in massive increases in caspase-3 activity, tubular apoptosis, and brush border injury (BBI) in mouse kidneys. During hibernation, the 13-lined ground squirrel (GS) cycles through repeated CI during torpor, followed by warm ischemia/reperfusion (WI) during interbout arousal (IBA). We sought to determine whether CI and WI during hibernation caused caspase-3 activation, tubular apoptosis, acute tubular necrosis, or BBI, and reduced renal function. We also determined whether protection was dependent on the stage of hibernation. METHODS Radiotelemeters were implanted in 1-year-old GS, and core body temperature was remotely monitored. GS kidneys at various stages of hibernation were subjected to ex vivo CI. RESULTS Tubular apoptosis was not detected and caspase-3-like activity was not different between hibernating and summer kidneys. Despite prolonged CI followed by WI and reperfusion, acute tubular necrosis and apoptosis did not occur in hibernating kidneys. BBI was absent in torpid kidneys but significantly increased in IBA kidneys and associated with an increase in caspase-3-like activity, suggesting that IBA kidneys are more susceptible to injury than summer or torpid kidneys. Renal function and urine concentrating ability diminished during torpor but returned during IBA. CONCLUSIONS Despite BBI, IBA kidneys clear serum creatinine and concentrate urine. Kidneys from both summer and hibernating animals tolerated ex vivo CI, confirming that protection from apoptotic and necrotic cell death is independent of the stage of hibernation. An understanding of how renal protection occurs during hibernation may help in understanding the pathophysiology of delayed graft function.
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Kim JG, Song YK, Jeon SY, Lim YJ, Ju H, Choi I, Chung CM. A New Efficient Synthetic Method for 3-Iodothyronamine and Its Potent Hypothermic Efficacy. CHINESE J CHEM 2011. [DOI: 10.1002/cjoc.201180382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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41
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Mulier KE, Lexcen DR, Luzcek E, Greenberg JJ, Beilman GJ. Treatment with beta-hydroxybutyrate and melatonin is associated with improved survival in a porcine model of hemorrhagic shock. Resuscitation 2011; 83:253-8. [PMID: 21864484 DOI: 10.1016/j.resuscitation.2011.08.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Revised: 08/04/2011] [Accepted: 08/05/2011] [Indexed: 01/10/2023]
Abstract
INTRODUCTION The neuroprotective ketone β-hydroxybutyrate (BHB) and the antioxidant melatonin have been found at elevated levels in hibernating mammals. Previous studies in rat models of hemorrhagic shock have suggested a benefit. We compared infusion of 4M BHB and 43 mM melatonin (BHB/M) to 4M sodium chloride and 20% DMSO (control solution) to evaluate for potential benefits in porcine hemorrhagic shock. METHODS Hemorrhagic shock was induced to obtain systolic blood pressures <50 mmHg for 60 min. Pigs were treated with a bolus of either BHB/M (n=9) or control solution (n=8) followed by 4-h infusion of the either BHB/M or control solution. All animals were then resuscitated for 20 h after shock. Physiological data were continually recorded, and blood samples were taken at intervals throughout the experiment. Serum samples were analyzed via high resolution NMR for metabolomic response. RESULTS BHB/M treatment significantly increased 24-h survival time when compared to treatment with control solution (100% versus 62%; p=0.050), with a trend toward decreased volume of resuscitative fluid administered to animals receiving BHB/M. BHB/M-treated animals had lower base deficit and higher oxygen consumption when compared to animals receiving control solution. Serum metabolite profiles revealed increases in β-hydroxybutyrate (BHB), succinate, 2-oxovalerate and adipate with BHB/M treatment as compared with animals treated with control infusion. CONCLUSION Infusion of BHB/M conferred a survival benefit over infusion of control solution in hemorrhagic shock. BHB and its products of metabolism are identified in serum of animals subjected to shock and treated with BHB/M. Further preclinical studies are needed to clarify the mechanisms of action of this promising treatment strategy.
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Affiliation(s)
- Kristine E Mulier
- Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
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Colonna C, Dorati R, Conti B, Modena T, Biggiogera M, Spedito A, Genta I. Induction of an in vitro reversible hypometabolism through chitosan-based nanoparticles. J Microencapsul 2011; 28:229-39. [PMID: 21545314 DOI: 10.3109/02652048.2011.557746] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Chitosan-based nanoparticles (NPs) were prepared to promote intracellular sustained delivery of the synthetic delta opioid D-Ala(2)-D-Leu(5)-enkephalin (DADLE), prolonging peptide activity and inducing a safe and reversible hypometabolic state. MATERIALS AND METHODS NPs were prepared by combining ionotropic gelation and ultrasonication treatment. NP uptake studies and the effects of encapsulated DADLE on HeLa cells proliferation were tested by transmission electron microscopy (TEM) analysis, by immuno-fluorescence and immuno-cytochemistry. RESULTS DADLE-loaded NPs are produced with suitable characteristics, a satisfactory process yield (55.4% ± 2.4%) and encapsulation efficiency (64.6% ± 2.1%). NPs are effective in inducing a hypometabolic stasis at a 10(-4) M DADLE concentration. Moreover, as seen from the immunofluorescence study, the effect persists through the recovery period (72 h). Indeed, NPs labelled by anti-enkephalin antibody inside cell nucleus reassert that the in vivo release of the peptide can be prolonged with respect to the case of free peptide supply. CONCLUSION The nanoparticulate drug delivery system described seems to be effective in inducing and prolonging a sort of hibernation-like state in the cells.
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Affiliation(s)
- C Colonna
- Department of Drug Sciences, University of Pavia, Pavia, Italy
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Kim JG, Song YK, Jo YH, Yu MR, Ju HW, Choi IH, Chung CM. A New Efficient Synthetic Method for 3-Iodothyronamine Involving Sonication and its Potent Hypothermic Efficacy. B KOREAN CHEM SOC 2011. [DOI: 10.5012/bkcs.2011.32.4.1131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Kolomiytseva IK, Markevich LN, Ignat'ev DA, Bykova OV. Lipids of nuclear fractions from neurons and glia of rat neocortex under conditions of artificial hypobiosis. BIOCHEMISTRY (MOSCOW) 2011; 75:1132-8. [PMID: 21077832 DOI: 10.1134/s0006297910090063] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Lipid contents were studied in tissue and nuclei isolated from neurons and glia of neocortex of rats under conditions of normothermia and in the state of artificial hypobiosis caused by hypothermia-hypoxia-hypercapnia. Compared to the neocortex tissue, both nuclear fractions were fivefold impoverished in phospholipids and cholesterol and strongly enriched with mono- and diglycerides and fatty acids. The nuclear fractions from neurons and glia contained similar amounts of phospholipids, and only the cardiolipin content in the neuronal nuclei was lower than in the glial nuclei. The state of artificial hypobiosis in rats led to an increase in the cholesterol/phospholipids ratio (mol/mol) in the nuclei from the neurons and glia; amounts of cholesterol and sphingomyelin in the nuclei from the glia were increased. The increases in the cholesterol and sphingomyelin contents and in the cholesterol/phospholipids ratio suggest an involvement of lipid-dependent signaling systems of the nuclei in the functional response of mammalian neocortex cells to artificial hypobiosis.
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Affiliation(s)
- I K Kolomiytseva
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
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Ju H, So H, Ha K, Park K, Lee JW, Chung CM, Choi I. Sustained torpidity following multi-dose administration of 3-iodothyronamine in mice. J Cell Physiol 2011; 226:853-8. [DOI: 10.1002/jcp.22573] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Portt L, Norman G, Clapp C, Greenwood M, Greenwood MT. Anti-apoptosis and cell survival: a review. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2010; 1813:238-59. [PMID: 20969895 DOI: 10.1016/j.bbamcr.2010.10.010] [Citation(s) in RCA: 436] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2010] [Revised: 10/04/2010] [Accepted: 10/11/2010] [Indexed: 02/08/2023]
Abstract
Type I programmed cell death (PCD) or apoptosis is critical for cellular self-destruction for a variety of processes such as development or the prevention of oncogenic transformation. Alternative forms, including type II (autophagy) and type III (necrotic) represent the other major types of PCD that also serve to trigger cell death. PCD must be tightly controlled since disregulated cell death is involved in the development of a large number of different pathologies. To counter the multitude of processes that are capable of triggering death, cells have devised a large number of cellular processes that serve to prevent inappropriate or premature PCD. These cell survival strategies involve a myriad of coordinated and systematic physiological and genetic changes that serve to ward off death. Here we will discuss the different strategies that are used to prevent cell death and focus on illustrating that although anti-apoptosis and cellular survival serve to counteract PCD, they are nevertheless mechanistically distinct from the processes that regulate cell death.
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Affiliation(s)
- Liam Portt
- Department of Chemistry and Chemical Engineering, Royal Military College, Ontario, Canada
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Recent applications of a synthetic model of cytochrome c oxidase: beyond functional modeling. Inorg Chem 2010; 49:5798-810. [PMID: 20527796 DOI: 10.1021/ic100472p] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
This account reports recent developments of a functional model for the active site of cytochrome c oxidase (CcO). This CcO mimic not only performs the selective four-electron reduction of oxygen to water but also catalytically reduces oxygen using the biological one-electron reductant, cytochrome c. This functional model has been used to understand other biological reactions of CcO, for example, the interaction between the gaseous hormone, NO, and CcO. A mechanism for inactivating NO-CcO complexes is found to involve a reaction between oxygen and Cu(B). Moreover, NO is shown to be capable of protecting CcO from toxic inhibitors such as CN(-) and CO. Finally, this functional CcO model has been used to show how H(2)S could induce hibernation by reversibly inhibiting the oxygen binding step involved in respiration.
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Decréau RA, Collman JP, Hosseini A. Electrochemical applications. How click chemistry brought biomimetic models to the next level: electrocatalysis under controlled rate of electron transfer. Chem Soc Rev 2010; 39:1291-301. [DOI: 10.1039/b901972n] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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