Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Ebrahimkhani, Mo R.; Daneshmand, Ali; Mazumder, Aprotim; Allocca, Mariacarmela; Calvo, Jennifer A.; Abolhassani, Nona; Jhun, Iny; Muthupalani, Sureshkumar; Ayata, Cenk; Samson, Leona D.

doi:10.1073/pnas.1413582111

Cited by 41 publications

(40 citation statements)

References 61 publications

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“…Nevertheless, many previous studies show that there can be conditions of imbalanced BER, wherein downstream BER enzymes are unable to keep up with DNA glycosylases [42–44]. This can lead to an increase in the overall levels of SSBs, which can be converted to DSBs if closely opposed or if encountered by a replication fork [45–48]. Indeed the observation that influenza leads to an increase in the levels of single strand lesions in vitro (as measured by the alkaline comet assay, Fig.…”

Section: Resultsmentioning

confidence: 99%

Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration

Parrish

Chan

et al. 2015

Cell. Mol. Life Sci.

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Influenza viruses account for significant morbidity worldwide. Inflammatory responses, including excessive generation of reactive oxygen and nitrogen species (RONS), mediate lung injury in severe Influenza infections. However, the molecular basis of inflammation-induced lung damage is not fully understood. Here, we studied influenza H1N1 infected cells in vitro, as well as H1N1 infected mice, and we monitored molecular and cellular responses over the course of two weeks in vivo. We show that influenza induces DNA damage both when cells are directly exposed to virus in vitro (measured using the comet assay) and also when cells are exposed to virus in vivo (estimated via γH2AX foci). We show that DNA damage, as well as responses to DNA damage, persist in vivo until long after virus has been cleared, at times when there are inflammation associated RONS (measured by xanthine oxidase activity and oxidative products). The frequency of lung epithelial and immune cells with increased γH2AX foci is elevated in vivo, especially for dividing cells (Ki-67 positive) exposed to oxidative stress during tissue regeneration. Additionally, we observed a significant increase in apoptotic cells as well as increased levels of DSB repair proteins Ku70, Ku86 and Rad51 during the regenerative phase. In conclusion, results show that influenza induces DNA both in vitro and in vivo, and that DNA damage responses are activated, raising the possibility that DNA repair capacity may be a determining factor for tissue recovery and disease outcome.

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Section: Resultsmentioning

confidence: 99%

Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration

Parrish

Chan

et al. 2015

Cell. Mol. Life Sci.

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“…Previous studies investigating tissues and organs such as the brain, heart, kidney and retina have demonstrated that numerous free radicals are produced during IRI, when the endogenous radical scavengers cannot function appropriately, leading to cell damage (1,2). Therefore, investigating effective drugs that alleviate IRI-induced functional liver damage, and improve the postoperative survival rate, has become a research hotspot in the field of hepatic surgery.…”

Section: Introductionmentioning

confidence: 99%

Effects of melatonin on liver function and lipid peroxidation in a rat model of hepatic ischemia/reperfusion injury

Deng

Liu

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The present study aimed to investigate the effects of melatonin (MT) on liver function and lipid peroxidation following hepatic ischemia-reperfusion injury (IRI). A total of 66 male Sprague-Dawley rats were randomly assigned into three groups: Normal control (N) group, ischemia-reperfusion (IR) group and the MT-treated group. A hepatic IRI model was developed by blocking the first porta hepatis, and subsequently restoring hepatic blood inflow after 35 min. Following reperfusion, changes in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were detected by a chemical method at various time points. In the MT group, the MDA levels were significantly reduced (P<0.05) at all time points, as compared with the IR group. Furthermore, SOD activity was significantly increased (P<0.05) in the MT group, as compared with the IR group at all time points; and the levels of GSH in the MT group were significantly higher (P<0.05) than those of the IR group at 2, 4, and 8 h post-reperfusion. The levels of ALT, AST and LDH were significantly reduced in the MT group at each time point, as compared with that of the IR group (P<0.05). In conclusion, MT exhibits potent antioxidant properties that may create favorable conditions for the recovery of liver function following IRI. IntroductionIn order to effectively control bleeding during hepatobiliary surgery, hepatic portal occlusion is often used, as it can temporarily interrupt the portal vein and hepatic artery inflow. This method is widely accepted since it is clinically simple, practical and effective; however, there is an inherent risk of subsequent liver ischemia-reperfusion injury (IRI). Therefore, in recent years, clinical research in the field of hepatic surgery has focused on how to reduce blood loss and improve the safety of hepatic portal occlusion, whilst simultaneously reducing the risk of liver IRI.Previous studies investigating tissues and organs such as the brain, heart, kidney and retina have demonstrated that numerous free radicals are produced during IRI, when the endogenous radical scavengers cannot function appropriately, leading to cell damage (1,2). Therefore, investigating effective drugs that alleviate IRI-induced functional liver damage, and improve the postoperative survival rate, has become a research hotspot in the field of hepatic surgery. Melatonin (MT) is a neural endocrine hormone that is secreted by the pineal gland (PG), which exerts known antioxidant, antitoxic, anti-stress and anti-inflammatory effects (3,4). Previous studies have demonstrated that MT has a protective role in IRI of the brain, heart, kidney and retina (5); however, its protective effects in liver IRI and the underlying mechanism require further research. An animal model of hepatic portal occlusion was used in the present study. MT was administered in advance, and the influence and significance of MT on antioxidant capacity, lipid peroxidation ...

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“…PARP1 inhibition has been shown to be beneficial in inflammatory diseases, such as diabetes, asthma and atherosclerosis (Ebrahimkhani et al, 2014; Sperling et al, 2013), through a variety of means, including the regulation of transcription factors, cytokines, adhesion factors and inflammatory mediators (Cummings et al, 2014; Jia et al, 2014; Stampfer, 2006). NF-κB, an inflammation mediator, was determined as a target for PARP1 activity (Godyn et al, 2016).…”

Section: Dna Repair Defects In Admentioning

confidence: 99%

Genome instability in Alzheimer disease

Song

Croteau

et al. 2017

Mechanisms of Ageing and Development

101

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component

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Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Cited by 41 publications

References 61 publications

Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration

Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration

Effects of melatonin on liver function and lipid peroxidation in a rat model of hepatic ischemia/reperfusion injury

Genome instability in Alzheimer disease

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