The involvement of radiofrequency electromagnetic fields (RF-EMF) in the neurodegenerative disease, especially Alzheimer’s disease (AD), has received wide consideration, however, outcomes from several researches have not shown consistency. In this study, we determined whether RF-EMF influenced AD pathology in vivo using Tg-5xFAD mice as a model of AD-like amyloid β (Aβ) pathology. The transgenic (Tg)-5xFAD and wild type (WT) mice were chronically exposed to RF-EMF for 8 months (1950 MHz, SAR 5W/kg, 2 hrs/day, 5 days/week). Notably, chronic RF-EMF exposure significantly reduced not only Aβ plaques, APP, and APP carboxyl-terminal fragments (CTFs) in whole brain including hippocampus and entorhinal cortex but also the ratio of Aβ42 and Aβ40 peptide in the hippocampus of Tg-5xFAD mice. We also found that parenchymal expression of β-amyloid precursor protein cleaving enzyme 1(BACE1) and neuroinflammation were inhibited by RF-EMF exposure in Tg-5xFAD. In addition, RF-EMF was shown to rescue memory impairment in Tg-5xFAD. Moreover, gene profiling from microarray data using hippocampus of WT and Tg-5xFAD following RF-EMF exposure revealed that 5 genes (Tshz2, Gm12695, St3gal1, Isx and Tll1), which are involved in Aβ, are significantly altered inTg-5xFAD mice, exhibiting different responses to RF-EMF in WT or Tg-5xFAD mice; RF-EMF exposure in WT mice showed similar patterns to control Tg-5xFAD mice, however, RF-EMF exposure in Tg-5xFAD mice showed opposite expression patterns. These findings indicate that chronic RF-EMF exposure directly affects Aβ pathology in AD but not in normal brain. Therefore, RF-EMF has preventive effects against AD-like pathology in advanced AD mice with a high expression of Aβ, which suggests that RF-EMF can have a beneficial influence on AD.
Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.
Glioblastoma (GBM) is a largely fatal and highly angiogenic malignancy with a median patient survival of just over 1 year with radiotherapy (RT). The effects of RT on GBM remain unclear, although increasing evidence suggests that RT-induced alterations in the brain microenvironment affect the recurrence and aggressiveness of GBM. Glioma stem cells (GSCs) in GBM are resistant to conventional therapies, including RT. This study aimed to investigate the effect of radiation on tumor growth and the GSC microenvironment in a mouse model of glioma. To evaluate the growth-inhibitory effects of ionizing radiation on GSCs, tumor volume was measured via anatomical magnetic resonance imaging (MRI) after the intracranial injection of 1 × 104 human patient-derived GSCs (83NS cells), which exhibit marked radioresistance. When a tumor mass of ~5 mm3 was detected in each animal, 10 Gy of cranial irradiation was administered. Tumor progression was observed in the orthotopic xenografted GSC tumor (primary tumor) from a detectable tumor mass (5 mm3) to a lethal tumor mass (78 mm3) in ~7 d in the non-irradiated group. In the RT group, tumor growth was halted for almost 2 weeks after administering 10 Gy cranial irradiation, with tumor growth resuming thereafter and eventually approaching a lethal mass (56 mm3) 21 d after radiation. Radiation therapy yielded good therapeutic effects, with a 2-fold increase in GSC glioma survival; however, tumor relapse after RT resulted in higher mortality for the mice with a smaller tumor volume (p = 0.029) than the non-irradiated tumor-bearing mice. Moreover, tumor regrowth after IR resulted in different phenotypes associated with glioma aggressiveness compared with the non-irradiated mice; the apparent diffusion coefficient by diffusion MRI decreased significantly (p < 0.05, 0 Gy vs. 10 Gy) alongside decreased angiogenesis, abnormal vascular dilatation, and upregulated CD34, VWF, AQP1, and AQP4 expression in the tumor. These findings demonstrate that radiation affects GSCs in GBM, potentially resulting in therapeutic resistance by changing the tumor microenvironment. Thus, the results of this study suggest potential therapeutic targets for overcoming the resistance of GBMs to RT.
Liver damage upon exposure to ionizing radiation, whether accidental or because of therapy can contribute to liver dysfunction. Currently, radiation therapy is used for various cancers including hepatocellular carcinoma; however, the treatment dose is limited by poor liver tolerance to radiation. Furthermore, reliable biomarkers to predict liver damage and associated side-effects are unavailable. Here, we investigated fibrinogen-like 1 (FGL1)-expression in the liver and plasma after radiation exposure. We found that 30 Gy of liver irradiation (IR) induced cell death including apoptosis, necrosis, and autophagy, with fibrotic changes in the liver occurring during the acute and subacute phase in mice. Moreover, FGL1 expression pattern in the liver following IR was associated with liver damage represented by injury-related proteins and oxidative stress markers. We confirmed the association between FGL1 expression and hepatocellular injury by exposing human hepatocytes to radiation. To determine its suitability, as a potential biomarker for radiation-induced liver injury, we measured FGL1 in the liver tissue and the plasma of mice following total body irradiation (TBI) or liver IR. In TBI, FGL1 showed the highest elevation in the liver compared to other major internal organs including the heart, lung, kidney, and intestine. Notably, plasma FGL1 showed good correlation with radiation dose by liver IR. Our data revealed that FGL1 upregulation indicates hepatocellular injury in response to IR. These results suggest that plasma FGL1 may represent a potential biomarker for acute and subacute radiation exposure to the liver.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease. In this study, to investigate the effect of microglial elimination on AD progression, we administered PLX3397, a selective colony-stimulating factor 1 receptor inhibitor, to the mouse model of AD (5xFAD mice). Amyloid-beta (Aβ) deposition and amyloid precursor protein (APP), carboxyl-terminal fragment β, ionized calcium-binding adaptor molecule 1, synaptophysin, and postsynaptic density (PSD)-95 levels were evaluated in the cortex and hippocampus. In addition, the receptor density changes in dopamine D2 receptor (D2R) and metabotropic glutamate receptor 5 were evaluated using positron emission tomography (PET). D2R, tyrosine hydroxylase (TH), and dopamine transporter (DAT) levels were analyzed in the brains of Tg (5xFAD) mice using immunohistochemistry. PLX3397 administration significantly decreased Aβ deposition following microglial depletion in the cortex and hippocampus of Tg mice. In the neuro-PET studies, the binding values for D2R in the Tg mice were lower than those in the wild type mice; however, after PLX3397 treatment, the binding dramatically increased. PLX3397 administration also reversed the changes in synaptophysin and PSD-95 expression in the brain. Furthermore, the D2R and TH expression in the brains of Tg mice was significantly lower than that in the wild type; however, after PLX3397 administration, the D2R and TH levels were significantly higher than those in untreated Tg mice. Thus, our findings show that administering PLX3397 to aged 5xFAD mice could prevent amyloid pathology, concomitant with the rescue of dopaminergic signaling, suggesting that targeting microglia may serve as a useful therapeutic option for neurodegenerative diseases, including AD.
The increased use of mobile phones has generated public concern about the impact of radiofrequency electromagnetic fields (RF‐EMF) on health. In the present study, we investigated whether RF‐EMFs induce molecular changes in amyloid precursor protein (APP) processing and amyloid beta (Aβ)‐related memory impairment in the 5xFAD mouse, which is a widely used amyloid animal model. The 5xFAD mice at the age of 1.5 months were assigned to two groups (RF‐EMF‐ and sham‐exposed groups, eight mice per group). The RF‐EMF group was placed in a reverberation chamber and exposed to 1950 MHz electromagnetic fields for 3 months (SAR 5 W/kg, 2 h/day, 5 days/week). The Y‐maze, Morris water maze, and novel object recognition memory test were used to evaluate spatial and non‐spatial memory following 3‐month RF‐EMF exposure. Furthermore, Aβ deposition and APP and carboxyl‐terminal fragment β (CTFβ) levels were evaluated in the hippocampus and cortex of 5xFAD mice, and plasma levels of Aβ peptides were also investigated. In behavioral tests, mice that were exposed to RF‐EMF for 3 months did not exhibit differences in spatial and non‐spatial memory compared to the sham‐exposed group, and no apparent change was evident in locomotor activity. Consistent with behavioral data, RF‐EMF did not alter APP and CTFβ levels or Aβ deposition in the brains of the 5xFAD mice. These findings indicate that 3‐month RF‐EMF exposure did not affect Aβ‐related memory impairment or Aβ accumulation in the 5xFAD Alzheimer's disease model. Bioelectromagnetics. 37:391–399, 2016. © 2016 The Authors Bioelectromagnetics published by Wiley Periodicals, Inc. on behalf of Bioelectromagnetics Society.
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