Oxidative Stress-induced miR-27a Targets the Redox gene Nrf2 in Diabetic Embryopathy

nano particles induce βA radical formation which can lead to βA oligomerization, and therefore contributes to AD pathogenesis.

89 Oxidative Stress-induced miR-27a Targets the Redox gene Nrf2 in Diabetic

DOI: 10.1016/j.freeradbiomed.2017.10.100

Embryopathy Daoyin Dong1, Yang Zhao1, Albert Reece1, Ashely R. Wang1, and Peixin Yang1

88

1

Effect of Acute Voluntary Exercise on Expression and Oxidative Modification of Low Density Lipoprotein Receptor-Related Protein 1 in Brain of Wild Type Mice as a Function of Age Debra Boyd-Kimball , Katelyn Gonczy , Benjamin Lewis , and Thomas Mason1 1

1

Low density lipoprotein receptor-related protein 1 (LRP1) is a type I membrane protein expressed in multiple cell types in the central nervous system including endothelial cells, vascular smooth muscle cells, pericytes, astrocytes, and neurons. LRP1 acts as an important efflux transporter of amyloid β-peptide 1-42 (Aβ42) across the blood-brain barrier from brain to blood. Expression of LRP1 and efflux of Aβ42 are both significantly decreased in Alzheimer’s Disease (AD) brain. LRP1 is oxidatively modified by the lipid peroxidation product 4-hydroxy-2-trans-nonenal (HNE) AD

hippocampus

(NTDs), and oxidative stress is a causal factor for maternal diabetes-induces NTDs. The redox gene Nrf2 (nuclear factorerythroid 2-related factor 2) is the master regulator of the cellular antioxidant system.

suggesting

that

Aβ42-mediated

oxidative stress may result in oxidative modification of its own transporter decreasing the clearance of Aβ42 in AD brain. Exercise has been shown to increase the capacity of the brain to tolerate oxidation damage. In this study, the effect of acute voluntary exercise on expression and oxidative modification of LRP1 in brain of 5, 10, and 22 month old wild type mice was examined. DOI: 10.1016/j.freeradbiomed.2017.10.101

whether maternal diabetes inhibits Nrf2 expression and Nrf2-controlled antioxidant genes through the redoxsensitive miR-27a.

University of Mount Union, USA

in

Background: Maternal diabetes induces neural tube defects

Objective: In the present study, we aimed to determine

1

1

University of Maryland School of Medicine, USA

Study design: We used a well-established type 1 diabetic embryopathy mouse model induced by streptozotocin for our in vivo studies. Embryos at E8.5 were harvested for analysis of Nrf2, Nrf2-controlled antioxidant genes and miR27a expression. To determine if mitigating oxidative stress inhibits the increase of miR-27a and the decrease of Nrf2 expression, we induced diabetic embryopathy in SOD2 (mitochondrial-associated antioxidant gene)-overexpressing mice. This model exhibits reduced mitochondria reactive oxygen species even in the presence of hyperglycemia. To investigate the causal relationship between miR-27a and Nrf2 in vitro, we examined C17.2 neural stem cells under normal and high glucose conditions. Results: We observed that the mRNA and protein levels of Nrf2 were significantly decreased in E8.5 embryos from diabetic dams compared to those from nondiabetic dams. High glucose also significantly decreased Nrf2 expression in a dose- and time- dependent manner in cultured neural stem cells. Our data revealed that miR-27a was up-regulated in E8.5 embryos exposed to diabetes, and that high glucose increased miR-27a levels in a dose- and time-dependent manner in cultured neural stem cells. In addition, we found that a miR-27a inhibitor abrogated the inhibitory effect of high glucose on Nrf2 expression, and a miR-27a mimic suppressed Nrf2 expression in cultured neural stem cells. Furthermore, our data indicated that the Nrf2-controlled antioxidant enzymes glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cyteine ligase modifier subunit (GLCM), and glutathione S-transferase A1 (GSTA1) were

SfRBM 2017

71

downregulated by maternal diabetes in E8.5 embryos and

significantly accelerated the Purkinje cell loss and inclusion

high glucose in cultured neural stem cells. Inhibiting miR-

body formation, and increased amount of apoptotic cells

27a restored expression of GCLC, GLCM and GSTA1.

and necrotic cells. Electron microscopy further revealed a

Overexpressing SOD2 reversed the maternal diabetes-

breakdown of myelin sheath and deformed synapse in

induced increase of miR-27a and suppression of Nrf2 and

Palb2f/f;Atg7f/f; Wap-cre mice. Mechanistically, we found

Nrf2-controlled antioxidant enzymes.

markedly higher levels of DNA damage marker γH2AX and

Conclusions: Our study demonstrates that maternal diabetes-

DNA oxidation marker 8-oxo-dG in both Palb2 single and

induced oxidative stress increases miR-27a, which, in turn,

Palb2/Atg7 double deletion brains compared with Atg7

suppresses Nrf2 and its responsive antioxidant enzymes,

single deletion brain. Taken together, these findings suggest

resulting in diabetic embryopathy.

that PALB2 plays an important role in neurons by

Keywords: maternal diabetes, embryopathy, oxidative stress,

preventing

miR-27a, Nrf2

autophagy is required for the normal functioning and

DNA

damage

and

oxidative

stress,

and

survival of neurons in the face of DNA damage and oxidative stress elicited by the loss of PALB2.

DOI: 10.1016/j.freeradbiomed.2017.10.102

Acknowledgements: This work was supported by the National Cancer Institute grants R01CA188096 (Xia and White) and R01CA138804 (Xia).

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DOI: 10.1016/j.freeradbiomed.2017.10.103

PALB2 Synergizes with ATG7 to Suppress Neurodegeneration

91

Yanying Huo1, Amar Mahdi1, Eileen White1, and Bing Xia1 1

Rutgers Cancer Institute of New Jersey, Rutgers, the State

University of New Jersey, USA Autophagy is an intracellular self-digestion process that plays a critical role in maintaining neuronal homeostasis. PALB2

is

a

homologous

tumor

suppressor

recombination-based

protein DNA

Circadian Activation of Nrf2 in Astrocytes Tetsuro Ishii1, Eiji Warabi1, and Giovanni E Mann2

for

1

University of Tsukuba, Japan

redox

2

King's College London, United Kingdom

essential repair,

BDNF-p75NTR Signaling Axis Regulates

homeostasis and breast cancer suppression. We previously showed that deletion of Palb2 in the mouse mammary gland

Circadian clock genes regulate energy metabolism partly

using Cre recombinase driven by the whey acid protein

through neurotrophins. The low affinity neurotrophin

promoter (Wap-cre) led to mammary tumor development,

receptor p75NTR is a clock component directly regulated by

which was delayed in a low-autophagy background. To

the transcriptional factor Clock:Bmal1 complex. Brain-

further understand the role of autophagy in breast cancer

derived neurotrophic factor (BDNF) is expressed in brain

development, we co-deleted the essential autophagy gene

and plays a key role in coordinating metabolic interactions

Atg7 together with Palb2 using Wap-cre. Surprisingly, Wap-

between neurons and astrocytes. BDNF transduces signals

cre-driven deletion of Atg7 resulted in neurodegeneration

through TrkB and p75NTR receptors, and the circadian

evidenced by motor deficits, and combined deletion of Palb2

control of p75NTR leads to daily resetting of glucose and

and Atg7 led to a similar but much more severe phenotype

glycogen metabolism in astrocytes to accommodate their

so that the mice died before mammary tumor development.

functional interaction with neurons. Recent studies show

This was found to be due to a high level of 'leaky' expression

that the circadian clock controls Nrf2-regulated antioxidant

of

and

defense genes in mouse tissues. The protein level of Nrf2 in

immunohistochemical studies revealed that Atg7 deletion

mouse lungs at early light phase is about 5-fold higher than

caused aberrant accumulation of p62, loss of Purkinje cell in

that in the early dark phase. The Nrf2 gene has a E-box

the cerebellum, and progressive formation of inclusion

element

bodies

transcription. However, the differences in the mRNA levels

72

Wap-cre

in

in

neurons,

the

brain.

Co-deletion

Morphologic

of

Palb2

with

Atg7

SfRBM 2017

and

the

Clock:Bmal1

complex

stimulates