Dietary Selenium for the Mitigation of Radiation Injury: Effects of Selenium Dose Escalation and Timing of Supplementation

Sieber, Fritz; Muir, Sarah A.; Cohen, Eric P.; Fish, Brian L.; Mäder, Marylou; Schock, Ashley M.; Althouse, Bryan J.; Moulder, John E.

doi:10.1667/rr2456.1

Cited by 31 publications

(31 citation statements)

References 25 publications

(24 reference statements)

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“…A quantitative scoring system of radiation-induced renal histopathological changes previously developed by one of the coauthors for quantitative assessment of radiation nephropathy in rats (Moulder 1993, Sieber et al 2011) was modified to assess radiation nephropathy in this model. The characteristics listed in Table 1 and described below were scored directly from images obtained at a magnification of 50–400×.…”

Section: Methodsmentioning

confidence: 99%

Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS

Unthank¹,

Miller²,

Quickery³

et al. 2015

Health Physics

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The threat of radiation exposure from warfare or radiation accidents raises the need for appropriate animal models to study the acute and chronic effects of high dose rate radiation exposure. The goal of this study was to assess the late development of fibrosis in multiple organs (kidney, heart, and lung) in survivors of the C57BL/6 mouse model of the hematopoietic-acute radiation syndrome (H-ARS). Separate groups of mice for histological and functional studies were exposed to a single uniform total body dose between 8.53 and 8.72 Gy of gamma radiation from a 137Cs radiation source and studied 1–21 months later. Blood urea nitrogen levels were elevated significantly in the irradiated mice at 9 and 21 mo (from ~22 to 34 ± 3.8 and 69±6.0 mg/dl, p<0.01 vs non-irradiated controls) and correlated with glomerosclerosis (29±1.8% vs 64±9.7% of total glomeruli, p<0.01 vs non-irradiated controls). Glomerular tubularization and hypertrophy and tubular atrophy were also observed at 21 mo post-total body irradiation (TBI). An increase in interstitial, perivascular, pericardial and peri-bronchial fibrosis/collagen deposition was observed from ~9–21 mo post-TBI in kidney, heart and lung of irradiated mice relative to age-matched controls. Echocardiography suggested decreased ventricular volumes with a compensatory increase in left ventricular ejection fraction. The results indicate that significant delayed effects of acute radiation exposure occur in kidney, heart, and lung in survivors of the murine H-ARS TBI model which mirrors pathology detected in larger species and humans at higher radiation doses focused on specific organs.

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Section: Methodsmentioning

confidence: 99%

Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS

Unthank¹,

Miller²,

Quickery³

et al. 2015

Health Physics

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“…Positive effects could have been missed because of non-optimal choices of drug dose and schedules and/or by insufficient animal numbers. In addition, we cannot yet assume that agents that mitigate, or fail to [16,18,21] Enalapril at 2-5 mg/kg/day ACE inhibitor Multiple start times after irradiation [16,21] Ramipril at 0.1-2.5 mg/kg/day ACE inhibitor 4 hours after irradiation and continued [21] Lisinopril at 0.5-2.5 mg/kg/day ACE inhibitor Multiple start times after irradiation [21] High salt at 7.75 % in the diet Nutrient 7 days to 10 weeks after irradiation [16] Mycophenolate mofetil at 20 mg/kg/day a Anti-inflammatory 3.5 to 9.5 weeks after irradiation EET-A at 10 mg/kg/day a Epoxyeicosatrienoic acid analog 2 days after irradiation and continued L-155809 at 2-8 mg/kg/day Angiotensin type-I receptor blocker Multiple start times after irradiation [13,22] Losartan at 8.5 mg/kg/day Angiotensin type-I receptor blocker 10 days after irradiation and continued [18] Selenium at 200 mg/kg/day Nutrient 4 hours after irradiation and continued [23] EUK-207 at 2.5 mg/kg/day SOD-Catalase mimetic 3 to 11 weeks after irradiation [24] PD-123319 at 60 mg/kg/day Angiotensin type-II receptor blocker 3.5 to 11.5 weeks after irradiation [13,22] a Unpublished observation However, there does seem to be some reason to think that some mitigators (e.g., the ACE inhibitors) may not be either species-or organ-specific, as experimental [46][47][48] and clinical [30,49] studies indicate that ACE inhibitors can also successfully mitigate radiation-induced lung injury. In addition, ACE inhibitors and/or AII blockers can mitigate experimental radiation injury to the skin [50] and the brain [51][52][53].…”

Section: Discussionmentioning

confidence: 99%

“…1 NIH recommended terminology for therapeutic approaches to modification of normal tissue radiation injuries. Reprinted with permission from Stone et al [2] Selenium, as selenite or seleno-L-methionine, also mitigates radiation nephropathy [23]. Selenium supplementation was most effective when started within 2 to 4 h after irradiation; when it was delayed by 1 week, the mitigation benefit was less.…”

Section: Radiation Clinical Symptoms E R Pmentioning

confidence: 99%

Mitigation of normal tissue radiation injury: evidence from rat radiation nephropathy models

et al. 2015

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Normal tissue radiation injury is a common complication of radiation therapy and is also a major concern after accidental or belligerent radiation exposure, and until recently, it was deemed untreatable. Both experimental and clinical evidence now show that radiation injury can be alleviated by agents started after irradiation but before manifestation of that injury (a therapeutic approach called Bmitigation^). Mitigation of normal tissue injuries would improve clinical radiation therapy, and it will be an essential medical countermeasure for accidental or belligerent radiation exposures. In rat radiation nephropathy models over 30 potential mitigators have been tested, some (e.g., angiotensin converting enzyme inhibitors and angiotensin II receptor blockers) have been found to be quite effective, but many others appear ineffective, and a few have actually made injury worse. For the most part, work with the successful agents, and the agents that made radiation injury worse, is in the peer-reviewed literature. However, we have found it difficult to publish information on the agents that were ineffective, although we suspect that others have tried some of the same agents and also found them ineffective. Here, we review all agents we know of that have been tested to date in rat radiation nephropathy models, with the goal of helping to prevent needless duplication of studies.

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“…Drugs with NF-κB pathway suppressive and anti-inflammatory actions, such as angiotensin-converting enzyme and prostaglandin biosynthesis inhibitors, genistein and melatonin, can mitigate post-radiation fibrosis of kidney, lungs, and skin (Table 1) (Sklobovskaia et al 1984; Molteni et al 2001; Vasin et al 2004a; Day et al 2008; Sieber et al 2011; Medhora et al 2012; Kma et al 2012) and post-radiation myelosuppression of ARS (Davis et al 2007, 2008; Day et al 2013; Vasin et al 2014c). …”

Section: Reviewmentioning

confidence: 99%

Comments on the mechanisms of action of radiation protective agents: basis components and their polyvalence

Vasin

2014

SpringerPlus

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PurposeThese comments suggest a division of radiation protective agents on the grounds of their mechanism of action that increase the radio resistance of an organism.ConclusionGiven below is the division of radiation protective agents on the basis of their mechanism of action into 3 groups: 1) Radiation protective agents, with the implementation of radiation protective action taking place at the cellular level in the course of rapidly proceeding radiation-chemical reactions. At the same time, when the ionizing radiation energy is absorbed, these agents partially neutralize the “oxygen effect” as a radiobiological phenomenon, especially in the radiolysis of DNA; 2) Radiation protective agents that exert their effect at the system level by accelerating the post-radiation recovery of radiosensitive tissues through activation of a number of pro-inflammatory signaling pathways and an increase in the secretion of hematopoietic growth factors, including their use as mitigators in the early period after irradiation prior to the clinical development of acute radiation syndrome (ARS). 3) Radiomodulators including drugs and nutritional supplements that can elevate the resistance of the organism to adverse environmental factors, including exposure to ionization by means of modulating the gene expression through a hormetic effect of small doses of stressors and a “substrate” maintenance of adaptive changes, resulting in an increased antioxidant protection of the organism. Radiation protective agents having polyvalence in implementation of their action may simultaneously induce radioprotective effect by various routes with a prevalence of basis mechanisms of the action.

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Dietary Selenium for the Mitigation of Radiation Injury: Effects of Selenium Dose Escalation and Timing of Supplementation

Cited by 31 publications

References 25 publications

Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS

Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS

Mitigation of normal tissue radiation injury: evidence from rat radiation nephropathy models

Comments on the mechanisms of action of radiation protective agents: basis components and their polyvalence

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