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Items: 7

1.
Brain Sci. 2018 Feb 27;8(3). pii: E39. doi: 10.3390/brainsci8030039.

Abstraction and Idealization in Biomedicine: The Nonautonomous Theory of Acute Cell Injury.

Author information

1
Department of Physiology, Wayne State University, Detroit, MI 48201, USA. ddegraci@med.wayne.edu.
2
Department of Physics and Astronomy, Wayne State University, Detroit, MI 48201, USA. dr.fikatri@yahoo.co.id.
3
Department of Physiology, Wayne State University, Detroit, MI 48201, USA. dotaha@umich.edu.
4
Department of Physics and Astronomy, Wayne State University, Detroit, MI 48201, USA. fp4165@wayne.edu.
5
Department of Physics and Astronomy, Wayne State University, Detroit, MI 48201, USA. fy1826@wayne.edu.
6
Department of Physics and Astronomy, Wayne State University, Detroit, MI 48201, USA. huang@wayne.edu.

Abstract

Neuroprotection seeks to halt cell death after brain ischemia and has been shown to be possible in laboratory studies. However, neuroprotection has not been successfully translated into clinical practice, despite voluminous research and controlled clinical trials. We suggested these failures may be due, at least in part, to the lack of a general theory of cell injury to guide research into specific injuries. The nonlinear dynamical theory of acute cell injury was introduced to ameliorate this situation. Here we present a revised nonautonomous nonlinear theory of acute cell injury and show how to interpret its solutions in terms of acute biomedical injuries. The theory solutions demonstrate the complexity of possible outcomes following an idealized acute injury and indicate that a "one size fits all" therapy is unlikely to be successful. This conclusion is offset by the fact that the theory can (1) determine if a cell has the possibility to survive given a specific acute injury, and (2) calculate the degree of therapy needed to cause survival. To appreciate these conclusions, it is necessary to idealize and abstract complex physical systems to identify the fundamental mechanism governing the injury dynamics. The path of abstraction and idealization in biomedical research opens the possibility for medical treatments that may achieve engineering levels of precision.

KEYWORDS:

acute cell injury; brain ischemia; cell death; neuroprotection; nonautonomous differential equation; preconditioning

Conflict of interest statement

The authors declare no conflict of interest.

2.
Transl Stroke Res. 2018 Jun;9(3):251-257. doi: 10.1007/s12975-017-0586-7. Epub 2017 Nov 10.

Disease of mRNA Regulation: Relevance for Ischemic Brain Injury.

Author information

1
Department of Physiology, and the Center for Molecular Medicine and Genetics, Wayne State University, 4116 Scott Hall, 540 E. Canfield, Detroit, MI, 48201, USA. ddegraci@med.wayne.edu.

Abstract

In this mini-review we give an overview of the role of mRNA-binding proteins and their associated messenger ribonucleoprotein complexes (mRNPs) in several disease states, and bring this information to bear on the pathophysiology of brain ischemia. One conclusion reached is that mRNPs may play a causal role in proteotoxicity instead of being merely passive targets. Ischemia therapies targeting mRNPs have advantages over targeting single pathways, but the behavior of mRNPs needs to be considered in the design of therapies.

KEYWORDS:

ARE mRNA; Brain ischemia and reperfusion; ELAV; HuR; Stress granule; mRNA regulation

3.
Wiley Interdiscip Rev RNA. 2017 Jul;8(4). doi: 10.1002/wrna.1415. Epub 2017 Jan 17.

Regulation of mRNA following brain ischemia and reperfusion.

Author information

1
Department of Physiology, Wayne State University, Detroit, MI, USA.

Abstract

There is growing appreciation that mRNA regulation plays important roles in disease and injury. mRNA regulation and ribonomics occur in brain ischemia and reperfusion (I/R) following stroke and cardiac arrest and resuscitation. It was recognized over 40 years ago that translation arrest (TA) accompanies brain I/R and is now recognized as part of the intrinsic stress responses triggered in neurons. However, neuron death correlates to a prolonged TA in cells fated to undergo delayed neuronal death (DND). Dysfunction of mRNA regulatory processes in cells fated to DND prevents them from translating stress-induced mRNAs such as heat shock proteins. The morphological and biochemical studies of mRNA regulation in postischemic neurons are discussed in the context of the large variety of molecular damage induced by ischemic injury. Open issues and areas of future investigation are highlighted. A sober look at the molecular complexity of ischemia-induced neuronal injury suggests that a network framework will assist in making sense of this complexity. The ribonomic network sits between the gene network and the various protein and metabolic networks. Thus, targeting the ribonomic network may prove more effective at neuroprotection than targeting specific molecular pathways, for which all efforts have failed to the present time to stop DND in stroke and after cardiac arrest. WIREs RNA 2017, 8:e1415. doi: 10.1002/wrna.1415 For further resources related to this article, please visit the WIREs website.

PMID:
28097803
DOI:
10.1002/wrna.1415
[Indexed for MEDLINE]
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4.
J Cereb Blood Flow Metab. 2017 Apr;37(4):1494-1507. doi: 10.1177/0271678X16657572. Epub 2016 Jan 1.

Embryonic lethal abnormal vision proteins and adenine and uridine-rich element mRNAs after global cerebral ischemia and reperfusion in the rat.

Author information

1
1 Department of Physiology, Wayne State University, Detroit, USA.
2
2 Center for Molecular Medicine and Genetics, Wayne State University, Detroit, USA.

Abstract

Prolonged translation arrest correlates with delayed neuronal death of hippocampal CA1 neurons following global cerebral ischemia and reperfusion. Many previous studies investigated ribosome molecular biology, but mRNA regulatory mechanisms after brain ischemia have been less studied. Here we investigated the embryonic lethal abnormal vision/Hu isoforms HuR, HuB, HuC, and HuD, as well as expression of mRNAs containing adenine and rich uridine elements following global ischemia in rat brain. Proteomics of embryonic lethal abnormal vision immunoprecipitations or polysomes isolated from rat hippocampal CA1 and CA3 from controls or following 10 min ischemia plus 8 h of reperfusion showed distinct sets of mRNA-binding proteins, suggesting differential mRNA regulation in each condition. Notably, HuB, HuC, and HuD were undetectable in NIC CA1. At 8 h reperfusion, polysome-associated mRNAs contained 46.1% of ischemia-upregulated mRNAs containing adenine and rich uridine elements in CA3, but only 18.7% in CA1. Since mRNAs containing adenine and rich uridine elements regulation are important to several cellular stress responses, our results suggest CA1 is disadvantaged compared to CA3 in coping with ischemic stress, and this is expected to be an important contributing factor to CA1 selective vulnerability. (Data are available via ProteomeXchange identifier PXD004078 and GEO Series accession number GSE82146).

KEYWORDS:

Global brain ischemia and reperfusion; adenine and rich uridine elements mRNA; embryonic lethal abnormal vision; hippocampal CA1; mRNA regulation

PMID:
27381823
PMCID:
PMC5453468
DOI:
10.1177/0271678X16657572
[Indexed for MEDLINE]
Free PMC Article
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5.
Int Sch Res Notices. 2014 Oct 13;2014:859341. doi: 10.1155/2014/859341. eCollection 2014.

Inductive and Deductive Approaches to Acute Cell Injury.

Author information

1
Department of Physiology, Wayne State University, 4116 Scott Hall, 540 East Canfield Avenue, Detroit, MI 48201, USA.
2
Department of Physics and Astronomy, Wayne State University, Detroit, MI 48201, USA.

Abstract

Many clinically relevant forms of acute injury, such as stroke, traumatic brain injury, and myocardial infarction, have resisted treatments to prevent cell death following injury. The clinical failures can be linked to the currently used inductive models based on biological specifics of the injury system. Here we contrast the application of inductive and deductive models of acute cell injury. Using brain ischemia as a case study, we discuss limitations in inductive inferences, including the inability to unambiguously assign cell death causality and the lack of a systematic quantitative framework. These limitations follow from an overemphasis on qualitative molecular pathways specific to the injured system. Our recently developed nonlinear dynamical theory of cell injury provides a generic, systematic approach to cell injury in which attractor states and system parameters are used to quantitatively characterize acute injury systems. The theoretical, empirical, and therapeutic implications of shifting to a deductive framework are discussed. We illustrate how a deductive mathematical framework offers tangible advantages over qualitative inductive models for the development of therapeutics of acutely injured biological systems.

6.
Transl Stroke Res. 2013 Dec;4(6):604-17. doi: 10.1007/s12975-013-0274-1. Epub 2013 Aug 6.

mRNA redistribution during permanent focal cerebral ischemia.

Author information

1
Department of Physiology, Wayne State University School of Medicine, 4116 Scott Hall, 540 East Canfield Ave, Detroit, MI, 48201, USA.

Abstract

Translation arrest occurs in neurons following focal cerebral ischemia and is irreversible in penumbral neurons destined to die. Following global cerebral ischemia, mRNA is sequestered away from 40S ribosomal subunits as mRNA granules, precluding translation. Here, we investigated mRNA granule formation using fluorescence in situ histochemistry out to 8 h permanent focal cerebral ischemia using middle cerebral artery occlusion in Long Evans rats with and without diabetes. Neuronal mRNA granules colocalized with PABP, HuR, and NeuN, but not 40S or 60S ribosomal subunits, or organelle markers. The volume of brain with mRNA granule-containing neurons decreased exponentially with ischemia duration, and was zero after 8 h permanent focal cerebral ischemia or any duration of ischemia in diabetic rats. These results show that neuronal mRNA granule response has a limited range of insult intensity over which it is expressed. Identifying the limits of effective neuronal stress response to ischemia will be important for developing effective stroke therapies.

PMID:
24323415
PMCID:
PMC3864703
DOI:
10.1007/s12975-013-0274-1
[Indexed for MEDLINE]
Free PMC Article
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7.
Transl Stroke Res. 2013 Dec;4(6):589-603. doi: 10.1007/s12975-013-0273-2. Epub 2013 Aug 2.

HuR function and translational state analysis following global brain ischemia and reperfusion.

Author information

1
Department of Physiology, Wayne State University School of Medicine, 4116 Scott Hall, 540 East Canfield Ave, Detroit, MI, 48201, USA.

Abstract

Prolonged translation arrest in post-ischemic hippocampal CA1 pyramidal neurons precludes translation of induced stress genes and directly correlates with cell death. We evaluated the regulation of mRNAs containing adenine- and uridine-rich elements (ARE) by assessing HuR protein and hsp70 mRNA nuclear translocation, HuR polysome binding, and translation state analysis of CA1 and CA3 at 8 h of reperfusion after 10 min of global cerebral ischemia. There was no difference between CA1 and CA3 at 8 h of reperfusion in nuclear or cytoplasmic HuR protein or hsp70 mRNA, or HuR polysome association, suggesting that neither mechanism contributed to post-ischemic outcome. Translation state analysis revealed that 28 and 58 % of unique mRNAs significantly different between 8hR and NIC, in CA3 and CA1, respectively, were not polysome-bound. There was significantly greater diversity of polysome-bound mRNAs in reperfused CA3 compared to CA1, and in both regions, ARE-containing mRNAs accounted for 4-5 % of the total. These data indicate that posttranscriptional ARE-containing mRNA regulation occurs in reperfused neurons and contributes to post-ischemic outcome. Understanding the differential responses of vulnerable and resistant neurons to ischemia will contribute to the development of effective neuroprotective therapies.

PMID:
24323414
PMCID:
PMC3864748
DOI:
10.1007/s12975-013-0273-2
[Indexed for MEDLINE]
Free PMC Article
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