Deficient DNA repair exacerbates ethanol-initiated DNA oxidation and embryopathies in ogg1 knockout mice: gender risk and protection by a free radical spin trapping agent

The herbicide paraquat causes lung injury that is believed to be oxygen-radical mediated. To further characterize this injury and explore new methods of preventing it, we used the spin-trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) to identify the paraquat radical in lung tissue and to reduce the injury resulting from the subsequent generation of reactive oxygen species. The formation of a paraquat free radical by guinea pig lung was detected under anaerobic conditions by electron paramagnetic resonance spectrometry. Infused (25, 50, or 100 mg/kg) into guinea pig lungs (perfused at constant flow with Krebs solution containing 4% bovine serum albumin and ventilated with 95% O2-5% CO2), paraquat produced dose-dependent increases in peak airway pressure (Paw), mean pulmonary arterial perfusion pressure (Ppa), and wet-to-dry (W/D) lung weight ratio. At 100 mg/kg, paraquat increased Paw by 589.6 +/- 59.8% (mean +/- SE, n = 8) and W/D ratio from 5.33 +/- 0.07 to 6.29 +/- 0.11 (P less than 0.001). Pulmonary vascular leak index increased from 0.40 +/- 0.09 to 1.96 +/- 0.45 (P less than 0.02), without changes in pulmonary microvascular pressure. Perfusate concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha increased, but indomethacin did not reduce the injury. PBN (2.3 mM) markedly attenuated all evidence of lung injury, which was also reduced by catalase, mannitol, ethanol, and vitamin E.(ABSTRACT TRUNCATED AT 250 WORDS)

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Inhibition of the microsomal oxidation of ethanol and 1-butanol by the free-radical, spin-trapping agent 5,5-dimethyl-1-pyrroline-1-oxide

Archives of Biochemistry and Biophysics ◽

10.1016/0003-9861(80)90049-1 ◽

1980 ◽

Vol 204 (2) ◽

pp. 397-403 ◽

Cited By ~ 24

Author(s):

Arthur I. Cederbaum ◽

Gerald Cohen

Keyword(s):

Free Radical ◽

Spin Trapping ◽

Microsomal Oxidation ◽

Trapping Agent ◽

Oxidation Of Ethanol

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HPN-07, a free radical spin trapping agent, protects against functional, cellular and electrophysiological changes in the cochlea induced by acute acoustic trauma

PLoS ONE ◽

10.1371/journal.pone.0183089 ◽

2017 ◽

Vol 12 (8) ◽

pp. e0183089 ◽

Cited By ~ 5

Author(s):

Donald Ewert ◽

Ning Hu ◽

Xiaoping Du ◽

Wei Li ◽

Matthew B. West ◽

...

Keyword(s):

Free Radical ◽

Acoustic Trauma ◽

Spin Trapping ◽

Trapping Agent ◽

Acute Acoustic Trauma

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The spin trapping agent PBN stimulates H2O2-induced Erk and Src kinase activity in human neuroblastoma cells

Neuroreport ◽

10.1097/00001756-200206120-00016 ◽

2002 ◽

Vol 13 (8) ◽

pp. 1057-1061 ◽

Cited By ~ 16

Author(s):

Pelin Kelicen ◽

Ippolita Cantuti-Castelvetri ◽

Can Pekiner ◽

K. Eric Paulson

Keyword(s):

Kinase Activity ◽

Neuroblastoma Cells ◽

Src Kinase ◽

Spin Trapping ◽

Human Neuroblastoma Cells ◽

Human Neuroblastoma ◽

Trapping Agent

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Direct evidence of iNOS-mediated in vivo free radical production and protein oxidation in acetone-induced ketosis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00015.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. E456-E462 ◽

Cited By ~ 28

Author(s):

Krisztian Stadler ◽

Marcelo G. Bonini ◽

Shannon Dallas ◽

Danielle Duma ◽

Ronald P. Mason ◽

...

Keyword(s):

Lipid Peroxidation ◽

Free Radical ◽

Nadph Oxidase ◽

Knockout Mice ◽

Protein Oxidation ◽

Ketone Bodies ◽

Free Radical Production ◽

Radical Production ◽

Inos Knockout Mice

Diabetic patients frequently encounter ketosis that is characterized by the breakdown of lipids with the consequent accumulation of ketone bodies. Several studies have demonstrated that reactive species are likely to induce tissue damage in diabetes, but the role of the ketone bodies in the process has not been fully investigated. In this study, electron paramagnetic resonance (EPR) spectroscopy combined with novel spin-trapping and immunological techniques has been used to investigate in vivo free radical formation in a murine model of acetone-induced ketosis. A six-line EPR spectrum consistent with the α-(4-pyridyl-1-oxide)- N-t-butylnitrone radical adduct of a carbon-centered lipid-derived radical was detected in the liver extracts. To investigate the possible enzymatic source of these radicals, inducible nitric oxide synthase (iNOS) and NADPH oxidase knockout mice were used. Free radical production was unchanged in the NADPH oxidase knockout but much decreased in the iNOS knockout mice, suggesting a role for iNOS in free radical production. Longer-term exposure to acetone revealed iNOS overexpression in the liver together with protein radical formation, which was detected by confocal microscopy and a novel immunospin-trapping method. Immunohistochemical analysis revealed enhanced lipid peroxidation and protein oxidation as a consequence of persistent free radical generation after 21 days of acetone treatment in control and NADPH oxidase knockout but not in iNOS knockout mice. Taken together, our data demonstrate that acetone administration, a model of ketosis, can lead to protein oxidation and lipid peroxidation through a free radical-dependent mechanism driven mainly by iNOS overexpression.

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Regulation of the cognitive aging process by the transcriptional repressor RP58

10.1101/2021.09.18.460879 ◽

2021 ◽

Author(s):

Tomoko Tanaka ◽

Shinobu Hirai ◽

Hiroyuki Manabe ◽

Kentaro Endo ◽

Hiroko Shimbo ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Knockout Mice ◽

Cognitive Aging ◽

Critical Role ◽

Harmful Effect ◽

Transcriptional Repressor ◽

Repair Pathway ◽

Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

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