Ciprofloxacin Therapy Results in Mitigation of ATP Loss after Irradiation Combined with Wound Trauma: Preservation of Pyruvate Dehydrogenase and Inhibition of Pyruvate Dehydrogenase Kinase 1

Swift, Joshua M.; Smith, Julian C.; Kiang, Juliann G.

doi:10.1667/rr13853.1

Cited by 13 publications

(15 citation statements)

References 35 publications

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“…As a result of all of these physiopathological changes, the causes of death underlying the mortality increases. Brain hemorrhage may have contributed to mortality since all dead mice had brain hemorrhage [10] and low in ATP [28, Kiang et al, unpublished], but 30-day surviving mice (1) did not have brain hemorrhage, (2) still exhibited low counts of lymphocytes [29], (3) bone marrow still had low cellularity [29], (4) GI still did not recover from the injury [27], (5) the brain displayed normal cellular ATP levels [Kiang et al, unpublished], and (6) most importantly, survived from the lethal exposure to radiation.…”

Section: Radiation Injurymentioning

confidence: 99%

“…Ionizing radiation activates PI3K/AKT and mitogen-activated protein kinase (MAPK) pathways [27, 83]. The PI3K/AKT pathway activates anti-apoptotic proteins [28, 84]. The MAPK pathways include extracellular signal-regulated kinase 1/2 (ERK1/2) activity [85], JNK [86], and p38 [87].…”

Section: Free Radical-mediated Apoptosismentioning

confidence: 99%

“…ATP is the main energy form for a variety of cellular processes, including DNA, RNA and protein synthesis, maintenance of the cytoskeleton, signaling, ion transport and repair. Herein, we reported that combined injury significantly reduced cellular ATP contents in ileum along with pancreas, brain, spleen, kidney and lung [28]. Radiation exerts its actions by (1) decreasing pyruvate dehydrogenase (PDH, an enzyme complex crucial to conversion of pyruvate to acetyl CoA for entrance into TCA cycle), (2) increasing pyruvate dehydrogenase kinase (PDK, an enzyme that phosphorylate PDH resulting in PDH becoming inactive) so that mitochondria lacks acetyl CoA as an fuel to generate ATP [28], and (3) remodeling mitochondria with fusion and fission leading to proptosis and autophagy [100].…”

Section: Radiation-induced Atp Reduction and Possible Signaling Involmentioning

confidence: 99%

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Radiation: a poly-traumatic hit leading to multi-organ injury

Kiang

Olabisi

2019

Cell Biosci

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The range of radiation threats we face today includes everything from individual radiation exposures to mass casualties resulting from a terrorist incident, and many of these exposure scenarios include the likelihood of additional traumatic injury as well. Radiation injury is defined as an ionizing radiation exposure inducing a series of organ injury within a specified time. Severity of organ injury depends on the radiation dose and the duration of radiation exposure. Organs and cells with high sensitivity to radiation injury are the skin, the hematopoietic system, the gastrointestinal (GI) tract, spermatogenic cells, and the vascular system. In general, acute radiation syndrome (ARS) includes DNA double strand breaks (DSB), hematopoietic syndrome (bone marrow cells and circulatory cells depletion), cutaneous injury, GI death, brain hemorrhage, and splenomegaly within 30 days after radiation exposure. Radiation injury sensitizes target organs and cells resulting in ARS. Among its many effects on tissue integrity at various levels, radiation exposure results in activation of the iNOS/NF-kB/NF-IL6 and p53/Bax pathways; and increases DNA single and double strand breaks, TLR signaling, cytokine concentrations, bacterial infection, cytochrome c release from mitochondria to cytoplasm, and possible PARP-dependent NAD and ATP-pool depletion. These alterations lead to apoptosis and autophagy and, as a result, increased mortality. In this review, we summarize what is known about how radiation exposure leads to the radiation response with time. We also describe current and prospective countermeasures relevant to the treatment and prevention of radiation injury.

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Section: Radiation Injurymentioning

confidence: 99%

Section: Free Radical-mediated Apoptosismentioning

confidence: 99%

Section: Radiation-induced Atp Reduction and Possible Signaling Involmentioning

confidence: 99%

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Radiation: a poly-traumatic hit leading to multi-organ injury

Kiang

Olabisi

2019

Cell Biosci

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“… 24 Radiation in combination with wound trauma causes cellular ATP depletion in the ileum, pancreas, brain, spleen, kidney, lung, and liver. 25 In that report, we found that combined radiation with wound trauma induced cellular ATP reduction by inhibiting pyruvate dehydrogenase and activating pyruvate dehydrogenase kinase 1. A similar result was found in mice after hemorrhage.…”

Section: Introductionmentioning

confidence: 92%

A novel therapy, using Ghrelin with pegylated G-CSF, inhibits brain hemorrhage from ionizing radiation or combined radiation injury

Kiang¹,

Smith²,

Anderson³

et al. 2019

PPIJ

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Medical treatment becomes challenging when complicated injuries arise from secondary reactive metabolic and inflammatory products induced by initial acute ionizing radiation injury (RI) or when combined with subsequent trauma insult(s) (CI). With such detrimental effects on many organs, CI exacerbates the severity of primary injuries and decreases survival. Previously, in a novel study, we reported that ghrelin therapy significantly improved survival after CI. This study aimed to investigate whether brain hemorrhage induced by RI and CI could be inhibited by ghrelin therapy with pegylated G-CSF (i.e., Neulasta®, an FDA-approved drug). B6D2F1 female mice were exposed to 9.5 Gy 60 Co-γ-radiation followed by 15% total-skin surface wound. Several endpoints were measured at several days. Brain hemorrhage and platelet depletion were observed in RI and CI mice. Brain hemorrhage severity was significantly higher in CI mice than in RI mice. Ghrelin therapy with pegylated G-CSF reduced the severity in brains of both RI and CI mice. RI and CI did not alter PARP and NF-κB but did significantly reduce PGC-1α and ghrelin receptors; the therapy, however, was able to partially recover ghrelin receptors. RI and CI significantly increased IL-6, KC, Eotaxin, G-CSF, MIP-2, MCP-1, MIP-1α, but significantly decreased IL-2, IL-9, IL-10, MIG, IFN-γ, and PDGF-bb; the therapy inhibited these changes. RI and CI significantly reduced platelet numbers, cellular ATP levels, NRF1/2, and AKT phosphorylation. The therapy significantly mitigated these CI-induced changes and reduced p53-mdm2 mediated caspase-3 activation. Our data are the first to support the view that Ghrelin therapy with pegylated G-CSF is potentially a novel therapy for treating brain hemorrhage after RI and CI.

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“…The mouse model has been used to study combined injury (radiation plus wound, burn, or hemorrhage) as well as for the evaluation of countermeasures effective against combined injuries (Kiang et al 2012(Kiang et al , 2014aElliott et al 2015). Efficacy of several radiation countermeasures such as captopril, PEGylated G-CSF, ghrelin, ciprofloxacin etc., has been established using the combined injury model in mice (Jiao et al 2009;Kiang et al 2010Kiang et al , 2014bSwift et al 2015).…”

Section: Micementioning

confidence: 99%

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

Singh

Seed²

2017

International Journal of Radiation Biology

142

103

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Purpose: The increasing global risk of nuclear and radiological accidents or attacks has driven renewed research interest in developing medical countermeasures to potentially injurious exposures to acute irradiation. Clinical symptoms and signs of a developing acute radiation injury, i.e. the acute radiation syndrome, are grouped into three sub-syndromes named after the dominant organ system affected, namely the hematopoietic, gastrointestinal, and neurovascular systems. The availability of safe and effective countermeasures against the above threats currently represents a significant unmet medical need. This is the first article within a three-part series covering the nature of the radiation subsyndromes, various animal models for radiation countermeasure development, and the agents currently approved by the United States Food and Drug Administration for countering the medical consequences of several of these prominent radiation exposure-associated syndromes. Conclusions: From the U.S. and global perspectives, biomedical research concerning medical countermeasure development is quite robust, largely due to increased government funding following the 9/11 incidence and subsequent rise of terrorist-associated threats. A wide spectrum of radiation countermeasures for specific types of radiation injuries is currently under investigation. However, only a few radiation countermeasures have been fully approved by regulatory agencies for human use during radiological/nuclear contingencies. Additional research effort, with additional funding, clearly will be needed in order to fill this significant, unmet medical health problem. ARTICLE HISTORY

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Ciprofloxacin Therapy Results in Mitigation of ATP Loss after Irradiation Combined with Wound Trauma: Preservation of Pyruvate Dehydrogenase and Inhibition of Pyruvate Dehydrogenase Kinase 1

Cited by 13 publications

References 35 publications

Radiation: a poly-traumatic hit leading to multi-organ injury

Radiation: a poly-traumatic hit leading to multi-organ injury

A novel therapy, using Ghrelin with pegylated G-CSF, inhibits brain hemorrhage from ionizing radiation or combined radiation injury

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

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