Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology submitted time 2016-05-11
Abstract: It has been established that exposure in the hypomagnetic field (HMF), which is one of the environmental factor of outer space, has adverse effects on animal and human behavior and brain function. Thus, it is necessary to develop appropriate counteract strategy to avoid the HMF-induced risks to the health of the astronauts during long-term and long-distance manned space mission. However, the physical and mental effects of the HMF in details still await systematic evaluation and the underlying mechanism remains elusive, so far. In this study, we constructed an HMF animal rearing system (<500 nT) and examined the effects of one-month HMF exposure on the circadian behavior, pain response and emotions in adult male C57BL/6 mice (4 similar to 6 weeks old, (20 +/- 2) g). The control animals were reared in the geomagnetic field (GMF). The HMF-exposed animals exhibited a prolonged alteration of the circadian drinking rhythm and a decrease in general activity, accompanied with an increase in thermal hyperalgesia. But the HMF did not induce obvious depression-like and anxiety-related behaviors. The serum noradrenalin concentration in HMF-exposed mice significantly decreased. These findings indicate that the HMF disturbs the behavior rhythm and the function of endocrine system, which probably leads to the subsequently weakened activities of the animal.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology submitted time 2016-05-11
Abstract: Growing evidence suggests a strong association between cardiovascular risk factors and incidence of Alzheimer disease (AD). Asymmetric dimethylarginine (ADMA), the endogenous nitric oxide synthase inhibitor, has been identified as an independent cardiovascular risk factor and is also increased in plasma of patients with AD. However, whether ADMA is involved in the pathogenesis of AD is unknown. In this study, we found that ADMA content was increased in a transgenic Caenorhabditis elegans beta-amyloid (A beta) overexpression model, strain CL2006, and in human SH-SY5Y cells overexpressing the Swedish mutant form of human A beta precursor protein (APPsw). Moreover, ADMA treatment exacerbated A beta-induced paralysis and oxidative stress in CL2006 worms and further elevated oxidative stress and A beta secretion in APPsw cells. Knockdown of type 1 protein arginine N-methyltransferase to reduce ADMA production failed to show a protective effect against A beta toxicity, but resulted in more paralysis in CL2006 worms as well as increased oxidative stress and A beta secretion in APPsw cells. However, overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) to promote ADMA degradation significantly attenuated oxidative stress and A beta secretion in APPsw cells. Collectively, our data support the hypothesis that elevated ADMA contributes to the pathogenesis of AD. Our findings suggest that strategies to increase DDAH1 activity in neuronal cells may be a novel approach to attenuating AD development. (C) 2014 Elsevier Inc. All rights reserved.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biophysics >> Neurosciences submitted time 2016-05-11
Abstract: All neurodegenerative diseases are associated with oxidative stress-induced neuronal death. Forkhead box O3a (FOXO3a) is a key transcription factor involved in neuronal apoptosis. However, how FOXO3a forms complexes and functions in oxidative stress processing remains largely unknown. In the present study, we show that histone deacetylase 2 (HDAC2) forms a physical complex with FOXO3a, which plays an important role in FOXO3a-dependent gene transcription and oxidative stress-induced mouse cerebellar granule neuron (CGN) apoptosis. Interestingly, we also found that HDAC2 became selectively enriched in the promoter region of the p21 gene, but not those of other target genes, and inhibited FOXO3a-mediated p21 transcription. Furthermore, we found that oxidative stress reduced the interaction between FOXO3a and HDAC2, leading to an increased histone H4K16 acetylation level in the p21 promoter region and upregulated p21 expression in a manner independent of p53 or E2F1. Phosphorylation of HDAC2 at Ser 394 is important for the HDAC2-FOXO3a interaction, and we found that cerebral ischemia/reperfusion reduced phosphorylation of HDAC2 at Ser 394 and mitigated the HDAC2-FOXO3a interaction in mouse brain tissue. Our study reveals the novel regulation of FOXO3a-mediated selective gene transcription via epigenetic modification in the process of oxidative stress-induced cell death, which could be exploited therapeutically.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology submitted time 2016-05-05
Abstract: Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38 alpha as a major substrate of c-Abl both in vitro and in vivo and c-Abl-mediated phosphorylation is critical for the dimerization of p38 alpha. Furthermore, p38 alpha inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38 alpha signaling may represent a therapeutic target for PD.
Peer Review Status:Awaiting Review