Protective effects of tauroursodeoxycholate against radiation-induced intestinal injury in a mouse model.

In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect.

Low-Dose Radiation Affects Cardiovascular Disease Risk in Human Aortic Endothelial Cells by Altering Gene Expression under Normal and Diabetic Conditions.

High doses of ionizing radiation can cause cardiovascular diseases (CVDs); however, the effects of <100 mGy radiation on CVD remain underreported. Endothelial cells (ECs) play major roles in cardiovascular health and disease, and their function is reduced by stimuli such as chronic disease, metabolic disorders, and smoking. However, whether exposure to low-dose radiation results in the disruption of similar molecular mechanisms in ECs under diabetic and non-diabetic states remains largely unknown; we aimed to address this gap in knowledge through the molecular and functional characterization of primary human aortic endothelial cells (HAECs) derived from patients with type 2 diabetes (T2D-HAECs) and normal HAECs in response to low-dose radiation. To address these limitations, we performed RNA sequencing on HAECs and T2D-HAECs following exposure to 100 mGy of ionizing radiation and examined the transcriptome changes associated with the low-dose radiation. Compared with that in the non-irradiation group, low-dose irradiation induced 243 differentially expressed genes (DEGs) (133 down-regulated and 110 up-regulated) in HAECs and 378 DEGs (195 down-regulated and 183 up-regulated) in T2D-HAECs. We also discovered a significant association between the DEGs and the interferon (IFN)-I signaling pathway, which is associated with CVD by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein−protein network analysis, and module analysis. Our findings demonstrate the potential impact of low-dose radiation on EC functions that are related to the risk of CVD.

Fibrinogen-Like Protein 1 Modulates Sorafenib Resistance in Human Hepatocellular Carcinoma Cells.

Despite liver cancer being the second-leading cause of cancer-related death worldwide, few systemic drugs have been approved. Sorafenib, the first FDA-approved systemic drug for unresectable hepatocellular carcinoma (HCC), is limited by resistance. However, the precise mechanisms underlying this phenomenon are unknown. Since fibrinogen-like 1 (FGL1) is involved in HCC progression and upregulated after anticancer therapy, we investigated its role in regulating sorafenib resistance in HCC. FGL1 expression was assessed in six HCC cell lines (HepG2, Huh7, Hep3B, SNU387, SNU449, and SNU475) using western blotting. Correlations between FGL1 expression and sorafenib resistance were examined by cell viability, colony formation, and flow cytometry assays. FGL1 was knocked-down to confirm its effects on sorafenib resistance. FGL1 expression was higher in HepG2, Huh7, and Hep3B cells than in SNU387, SNU449, and SNU475 cells; high FGL1-expressing HCC cells showed a lower IC50 and higher sensitivity to sorafenib. In Huh7 and Hep3B cells, FGL1 knockdown significantly increased colony formation by 61% (p = 0.0013) and 99% (p = 0.0002), respectively, compared to that in controls and abolished sorafenib-induced suppression of colony formation, possibly by modulating ERK and autophagy signals. Our findings demonstrate that sorafenib resistance mediated by FGL1 in HCC cells, suggesting FGL1 as a potential sorafenib-resistance biomarker and target for HCC therapy.

Therapeutic Effects of Aripiprazole in the 5xFAD Alzheimer's Disease Mouse Model.

Global aging has led to growing health concerns posed by Alzheimer's disease (AD), the most common type of dementia. Aripiprazole is an atypical FDA-approved anti-psychotic drug with potential against AD. To investigate its therapeutic effects on AD pathology, we administered aripiprazole to 5xFAD AD model mice and examined beta-amyloid (ßA)-induced AD-like phenotypes, including ßA production, neuroinflammation, and cerebral glucose metabolism. Aripiprazole administration significantly decreased ßA accumulation in the brains of 5xFAD AD mice. Aripiprazole significantly modified amyloid precursor protein processing, including carboxyl-terminal fragment ß and ßA, a disintegrin and metalloproteinase domain-containing protein 10, and beta-site APP cleaving enzyme 1, as determined by Western blotting. Neuroinflammation, as evidenced by ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein upregulation was dramatically inhibited, and the neuron cell layer of the hippocampal CA1 region was preserved following aripiprazole administration. In 18F-fluorodeoxyglucose positron emission tomography, after receiving aripiprazole, 5xFAD mice showed a significant increase in glucose uptake in the striatum, thalamus, and hippocampus compared to vehicle-treated AD mice. Thus, aripiprazole effectively alleviated ßA lesions and prevented the decline of cerebral glucose metabolism in 5xFAD AD mice, suggesting its potential for ßA metabolic modification and highlighting its therapeutic effect over AD progression.

Idiopathic chronic diarrhea associated with dysbiosis in a captive cynomolgus macaque (Macaca fascicularis).

Chronic inflammatory enteric diseases occur commonly in humans and animals, especially in captive bred macaques. However, information about the etiology of idiopathic chronic inflammatory diarrhea in cynomolgus monkeys is limited. In this paper, we reported the unusual case of idiopathic chronic diarrhea in a captive cynomolgus monkey based on microbial, imaging, and microbiome examinations.

Inhibition of Colony-Stimulating Factor 1 Receptor by PLX3397 Prevents Amyloid Beta Pathology and Rescues Dopaminergic Signaling in Aging 5xFAD Mice.

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 (Aß) deposition and amyloid precursor protein (APP), carboxyl-terminal fragment ß, 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 Aß 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.

Impact of Long-Term RF-EMF on Oxidative Stress and Neuroinflammation in Aging Brains of C57BL/6 Mice.

The expansion of mobile phone use has raised questions regarding the possible biological effects of radiofrequency electromagnetic field (RF-EMF) exposure on oxidative stress and brain inflammation. Despite accumulative exposure of humans to radiofrequency electromagnetic fields (RF-EMFs) from mobile phones, their long-term effects on oxidative stress and neuroinflammation in the aging brain have not been studied. In the present study, middle-aged C57BL/6 mice (aged 14 months) were exposed to 1950 MHz electromagnetic fields for 8 months (specific absorption rate (SAR) 5 W/kg, 2 h/day, 5 d/week). Compared with those in the young group, levels of protein (3-nitro-tyrosine) and lipid (4-hydroxy-2-nonenal) oxidative damage markers were significantly increased in the brains of aged mice. In addition, levels of markers for DNA damage (8-hydroxy-2'-deoxyguanosine, p53, p21, γH2AX, and Bax), apoptosis (cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1 (PARP-1)), astrocyte (GFAP), and microglia (Iba-1) were significantly elevated in the brains of aged mice. However, long-term RF-EMF exposure did not change the levels of oxidative stress, DNA damage, apoptosis, astrocyte, or microglia markers in the aged mouse brains. Moreover, long-term RF-EMF exposure did not alter locomotor activity in aged mice. Therefore, these findings indicate that long-term exposure to RF-EMF did not influence age-induced oxidative stress or neuroinflammation in C57BL/6 mice.

Possible involvement of hippocampal immediate-early genes in contextual fear memory deficit induced by cranial irradiation.

Cranial irradiation can trigger adverse effects on brain functions, including cognitive ability. However, the cellular and molecular mechanisms underlying radiation-induced cognitive impairments remain still unknown. Immediate-early genes (IEGs) are implicated in neuronal plasticity and the related functions (i.e., memory formation) in the hippocampus. The present study quantitatively assessed changes in the mRNA and protein levels of the learning-induced IEGs, including Arc, c-fos, and zif268, in the mouse hippocampus after cranial irradiation using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively. Mice (male, 8-week-old C57BL/6) received whole-brain irradiation with 0 or 10Gy of gamma-ray and, 2weeks later, contextual fear conditioning (CFC) was used to induce IEGs. In the CFC task, mice evaluated 2weeks after irradiation exhibited significant memory deficits compared with sham (0Gy)-irradiated controls. The levels of mRNA encoding IEGs were significantly upregulated in the hippocampus 10 and 30min after CFC training. The mRNA levels in the irradiated hippocampi were significantly lower than those in the sham-irradiated controls. The IEG protein levels were significantly increased in all hippocampal regions, including the hippocampal dentate gyrus, cornu ammonis (CA)1, and CA3, after CFC training. The CFC-induced upregulation of Arc and c-fos in 10Gy-irradiated hippocampi was significantly lower than that in sham-irradiated controls, although there were no significant differences in the protein levels of the learning-induced zif268 between sham-irradiated and 10Gy-irradiated hippocampi. Thus, cranial irradiation with 10Gy of gamma-ray impairs the induction of hippocampal IEGs (particularly Arc and c-fos) via behavioral contextual fear memory, and this disturbance may be associated with the memory deficits evident in mice after cranial irradiation, possibly through the dysregulation of neuronal plasticity during memory formation.

1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice.

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 (Aß)-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, Aß deposition and APP and carboxyl-terminal fragment ß (CTFß) levels were evaluated in the hippocampus and cortex of 5xFAD mice, and plasma levels of Aß 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 CTFß levels or Aß deposition in the brains of the 5xFAD mice. These findings indicate that 3-month RF-EMF exposure did not affect Aß-related memory impairment or Aß 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.

Cranial irradiation regulates CREB-BDNF signaling and variant BDNF transcript levels in the mouse hippocampus.

The brain can be exposed to ionizing radiation in various ways, and such irradiation can trigger adverse effects, particularly on learning and memory. However, the precise mechanisms of cognitive impairments induced by cranial irradiation remain unknown. In the hippocampus, brain-derived neurotrophic factor (BDNF) plays roles in neurogenesis, neuronal survival, neuronal differentiation, and synaptic plasticity. The significance of BDNF transcript variants in these contexts is becoming clearer. In the present study, both object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice were assessed 1 month after a single exposure to cranial irradiation (10 Gy) to evaluate hippocampus-related behavioral dysfunction following such irradiation. Furthermore, changes in the levels of BDNF, the cAMP-response element binding protein (CREB) phosphorylation, and BDNF transcript variants were measured in the hippocampus 1 month after cranial irradiation. On object recognition memory and contextual fear conditioning tasks, mice evaluated 1 month after irradiation exhibited significant memory deficits compared to sham-irradiated controls, but no apparent change was evident in locomotor activity. Both phosphorylated CREB and BDNF protein levels were significantly downregulated after irradiation of the hippocampus. Moreover, the levels of mRNAs encoding common BDNF transcripts, and exons IIC, III, IV, VII, VIII, and IXA, were significantly downregulated after irradiation. The reductions in CREB phosphorylation and BDNF expression induced by differential regulation of BDNF hippocampal exon transcripts may be associated with the memory deficits evident in mice after cranial irradiation.

Hippocampal dysfunctions caused by cranial irradiation: a review of the experimental evidence.

Cranial irradiation (IR) is commonly used for the treatment of brain tumors but may cause disastrous brain injury, especially in the hippocampus, which has important cognition and emotional regulation functions. Several preclinical studies have investigated the mechanisms associated with cranial IR-induced hippocampal dysfunction such as memory defects and depression-like behavior. However, current research on hippocampal dysfunction and its associated mechanisms, with the ultimate goal of overcoming the side effects of cranial radiation therapy in the hippocampus, is still very much in progress. This article reviews several in vivo studies on the possible mechanisms of radiation-induced hippocampal dysfunction, which may be associated with hippocampal neurogenesis, neurotrophin and neuroinflammation. Thus, this review may be helpful to gain new mechanistic insights into hippocampal dysfunction following cranial IR and provide effective strategies for potential therapeutic approaches for cancer patients receiving radiation therapy.

The ameliorative effect of silibinin against radiation-induced lung injury: protection of normal tissue without decreasing therapeutic efficacy in lung cancer.

BACKGROUND: Silibinin has been known for its role in anti-cancer and radio-protective effect. Radiation therapy for treating lung cancer might lead to late-phase pulmonary inflammation and fibrosis. Thus, this study aimed to investigate the effects of silibinin in radiation-induced lung injury with a mouse model. METHODS: In this study, we examined the ability of silibinin to mitigate lung injury in, and improve survival of, C57BL/6 mice given 13 Gy thoracic irradiation and silibinin treatments orally at 100 mg/kg/day for seven days after irradiation. In addition, Lewis lung cancer (LLC) cells were injected intravenously in C57BL/6 mice to generate lung tumor nodules. Lung tumor-bearing mice were treated with lung radiation therapy at 13 Gy and with silibinin at a dose of 100 mg/day for seven days after irradiation. RESULTS: Silibinin was shown to increase mouse survival, to ameliorate radiation-induced hemorrhage, inflammation and fibrosis in lung tissue, to reduce the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and to reduce inflammatory cell infiltration in the respiratory tract. In LLC tumor injected mice, lung tissue from mice treated with both radiation and silibinin showed no differences compared to lung tissue from mice treated with radiation alone. CONCLUSIONS: Silibinin treatment mitigated the radiation-induced lung injury possibly by reducing inflammation and fibrosis, which might be related with the improved survival rate. Silibinin might be a useful agent for lung cancer patients as a non-toxic complementary approach to alleviate the side effects by thorax irradiation.

Distinguish response of low-dose radiation with different dose-rate on gene expression of human coronary artery endothelial cells: a bioinformatic study based on transcriptomic sequencing.

PURPOSE: People are exposed to low-dose radiation in medical diagnosis, occupational, or life circumstances, but the effect of low-dose radiation on human health is still controversial. The biological effects of radiation below 100 mGy are still unproven. In this study, we observed the effects of low-dose radiation (100 mGy) on gene expression in human coronary artery endothelial cells (HCAECs) and its effect on molecular signaling. MATERIALS AND METHODS: HCAECs were exposed to 100 mGy ionizing radiation at 6 mGy/h (low-dose-rate) or 288 mGy/h (high-dose-rate). After 72 h, total RNA was extracted from sham or irradiated cells for Quant-Seq 3'mRNA-Seq, and bioinformatic analyses were performed using Metascape. Gene profiling was validated using qPCR. RESULTS: Compared to the non-irradiated control group, 100 mGy of ionizing radiation at 6 mGy/h altered the expression of 194 genes involved in signaling pathways related to heart contraction, blood circulation, and cardiac myofibril assembly differentially. However, 100 mGy at 288 mGy/h altered expression of 450 genes involved in cell cycle-related signaling pathways, including cell division, nuclear division, and mitosis differentially. Additionally, gene signatures responding to low-dose radiation, including radiation dose-specific gene profiles (HIST1H2AI, RAVER1, and POTEI) and dose-rate-specific gene profiles (MYL2 for the low-dose-rate and DHRS9 and CA14 for the high-dose-rate) were also identified. CONCLUSIONS: We demonstrated that 100 mGy low-dose radiation could alter gene expression and molecular signaling pathways at the low-dose-rate and the high-dose-rate differently. Our findings provide evidence for further research on the potential impact of low-dose radiation on cardiovascular function.

Low-Dose Radiation Therapy for Neurological Disorders: A Double-Edged Sword.

Radiation therapy targeting the central nervous system is widely utilized for the management of various brain tumors, significantly prolonging patient survival. Presently, investigations are assessing both clinical and preclinical applications of low-dose radiation (LDR) for the treatment of neuropathological conditions beyond tumor therapy. Special focus is given to refractory neurodegenerative diseases linked to neuroinflammation, such as Alzheimer's and Parkinson's diseases, where LDR has shown promising results. This comprehensive review examines the existing experimental data regarding the utilization of LDR in neurological disorders. It covers potential advantages in reducing neurodegenerative alterations and inflammation, as well as possible adverse effects, including neurological impairments. The review underscores the importance of the exposure protocol and the age at which LDR is administered in the context of the nervous system's pathological and physiological states, as these elements are crucial in determining LDR's therapeutic and toxic outcomes. The article concludes with a discussion on the future directions and challenges in optimizing LDR use, aiming to reduce toxicity while effectively managing neurological disorders.

Possible association of G6PC2 and MUC6 induced by low­dose­rate irradiation in mouse intestine with inflammatory bowel disease.

Although there are several types of radiation exposure, it is debated whether low­dose­rate (LDR) irradiation (IR) affects the body. Since the small intestine is a radiation­sensitive organ, the present study aimed to evaluate how it changes when exposed to LDR IR and identify the genes sensitive to these doses. After undergoing LDR (6.0 mGy/h) γ radiation exposure, intestinal RNA from BALB/c mice was extracted 1 and 24 h later. Mouse whole genome microarrays were used to explore radiation­induced transcriptional alterations. Reverse transcription­quantitative (RT­q) PCR was used to examine time­ and dose­dependent radiation responses. The histopathological status of the jejunum in the radiated mouse was not changed by 10 mGy of LDR IR; however, 23 genes were upregulated in response to LDR IR of the jejunum in mice after 1 and 24 h of exposure. Upregulated genes were selected to validate the results of the RNA sequencing analysis for RT­qPCR detection and results showed that only Na+/K+ transporting subunit α4, glucose­6­phosphatase catalytic subunit 2 (G6PC2), mucin 6 (MUC6) and transient receptor potential cation channel subfamily V member 6 levels significantly increased after 24 h of LDR IR. Furthermore, G6PC2 and MUC6 were notable genes induced by LDR IR exposure according to protein expression via western blot analysis. The mRNA levels of G6PC2 and MUC6 were significantly elevated within 24 h under three conditions: i) Exposure to LDR IR, ii) repeated exposure to LDR IR and iii) exposure to LDR IR in the presence of inflammatory bowel disease. These results could contribute to an improved understanding of immediate radiation reactions and biomarker development to identify radiation­susceptible individuals before histopathological changes become noticeable. However, further investigation into the specific mechanisms involving G6PC2 and MUC6 is required to accomplish this.

Low-dose-rate ionizing radiation affects innate immunity protein IFITM3 in a mouse model of Alzheimer's disease.

PURPOSE: Although the adverse health risks associated with low-dose radiation (LDR) are highly debated, relevant data on neuronal function following chronic LDR exposure are still lacking. MATERIALS AND METHODS: To confirm the effect of chronic LDR on the progression of Alzheimer's disease (AD), we investigated changes in behavior and neuroinflammation after radiation exposure in wild-type (WT) and 5xFAD (TG) mice, an animal model of AD. WT and TG mice, classified by genotyping, were exposed to low-dose-rate radiation for 112 days, with cumulative doses of 0, 0.1, and 0.3 Gy, then evaluated using the open-field and Y-maze behavioral function tests. Changes in the levels of APP processing- and neuroinflammation-related genes were also investigated. RESULTS: No apparent change was evident in either non-spatial memory function or locomotor activity, as examined by the Y-maze and open field tests, respectively. Although chronic LDR did not affect the levels of APP processing, gliosis (Iba1 and GFAP), or inflammatory cytokines (IL-1ß, IL-6, and TNF-α), the levels of IFN-γ were significantly downregulated in TG mice following LDR exposure. In an additional analysis, we examined the genes related to IFN signaling and found that the levels of interferon induced transmembrane protein 3 (IFITM3) were decreased significantly in TG mice following LDR with 0.1 or 0.3 Gy. CONCLUSIONS: Therefore, this study revealed the possibility that LDR could affect the progression of AD, which may be associated with decreased IFN-related signaling, especially IFITM3. Our findings suggest that further studies are required regarding the potential role of LDR in the progression of AD.

Long-term radiofrequency electromagnetic fields exposure attenuates cognitive dysfunction in 5×FAD mice by regulating microglial function.

We have previously found that long-term effects of exposure to radiofrequency electromagnetic fields in 5×FAD mice with severe late-stage Alzheimer's disease reduced both amyloid-ß deposition and glial activation, including microglia. To examine whether this therapeutic effect is due to the regulation of activated microglia, we analyzed microglial gene expression profiles and the existence of microglia in the brain in this study. 5×FAD mice at the age of 1.5 months were assigned to sham- and radiofrequency electromagnetic fields-exposed groups and then animals were exposed to 1950 MHz radiofrequency electromagnetic fields at a specific absorption rate of 5 W/kg for 2 hours/day and 5 days/week for 6 months. We conducted behavioral tests including the object recognition and Y-maze tests and molecular and histopathological analysis of amyloid precursor protein/amyloid-beta metabolism in brain tissue. We confirmed that radiofrequency electromagnetic field exposure for 6 months ameliorated cognitive impairment and amyloid-ß deposition. The expression levels of Iba1 (pan-microglial marker) and colony-stimulating factor 1 receptor (CSF1R; regulates microglial proliferation) in the hippocampus in 5×FAD mice treated with radiofrequency electromagnetic fields were significantly reduced compared with those of the sham-exposed group. Subsequently, we analyzed the expression levels of genes related to microgliosis and microglial function in the radiofrequency electromagnetic fields-exposed group compared to those of a CSF1R inhibitor (PLX3397)-treated group. Both radiofrequency electromagnetic fields and PLX3397 suppressed the levels of genes related to microgliosis (Csf1r, CD68, and Ccl6) and pro-inflammatory cytokine interleukin-1ß. Notably, the expression levels of genes related to microglial function, including Trem2, Fcgr1a, Ctss, and Spi1, were decreased after long-term radiofrequency electromagnetic field exposure, which was also observed in response to microglial suppression by PLX3397. These results showed that radiofrequency electromagnetic fields ameliorated amyloid-ß pathology and cognitive impairment by suppressing amyloid-ß deposition-induced microgliosis and their key regulator, CSF1R.

EFFECT OF ABDOMINAL IRRADIATION IN MICE MODEL OF INFLAMMATORY BOWEL DISEASE.

Inflammatory bowel diseases could be diagnosed in major measure by diagnostic imaging; however, radiation exposure in the intestine may also contribute to the progression of these pathologies. To better understand the impact of radiation in the presence of bowel disease, we administered dextran sodium sulfate (DSS) to C57BL/6 mice to induce colitis and exposed to radiation at abdominal area. We observed that abdominal irradiation (13 Gy) aggravates the DSS-induced decrease in survival rate (0%), body weight (74.54 ± 3.59%) and colon length (4.98 ± 0.14 cm). Additionally, abdominal irradiation markedly increased in colonic inflammation levels (3.16 ± 0.16) compared with that of DSS-induced sham mice. Furthermore, abdominal irradiation also increased the mRNA expression levels of inflammatory genes, such as cyclooxygenase-2 (13.10 folds), interleukin-6 (48.83 folds) and tumor necrosis factor-alpha (42.97 folds). We conclude that abdominal irradiation aggravates the detrimental effects of DSS-induced colitis in mice, which might be a useful guideline for inflammatory bowel disease patients.

Profiling of gene expression in the brain associated with anxiety-related behaviors in the chronic phase following cranial irradiation.

Although the brain is exposed to cranial irradiation in many clinical contexts, including malignant brain tumor therapy, such exposure can cause delayed neuropsychiatric disorders in the chronic phase. However, how specific molecular mechanisms are associated with irradiation-induced behavioral dysfunction, especially anxiety-like behaviors, is unclear. In the present study, we evaluated anxiety-like behaviors in adult C57BL/6 mice using the open-field (OF) and elevated plus maze (EPM) tests 3 months following single cranial irradiation (10 Gy). Additionally, by using RNA sequencing (RNA-seq), we analyzed gene expression profiles in the cortex and hippocampus of the adult brain to demonstrate the molecular mechanisms of radiation-induced brain dysfunction. In the OF and EPM tests, mice treated with radiation exhibited increased anxiety-like behaviors in the chronic phase. Gene expression analysis by RNA-seq revealed 89 and 106 differentially expressed genes in the cortex and hippocampus, respectively, following cranial irradiation. Subsequently, ClueGO and STRING analyses clustered these genes in pathways related to protein kinase activity, circadian behavior, and cell differentiation. Based on our expression analysis, we suggest that behavioral dysfunction following cranial irradiation is associated with altered expression of Cdkn1a, Ciart, Fos, Hspa5, Hspb1 and Klf10. These novel findings may provide potential genetic targets to investigate for the development of radioprotective agents.

Low Dose Rate Radiation Regulates M2-like Macrophages in an Allergic Airway Inflammation Mouse Model.

We investigated the effects of low dose rate radiation (LDR) on M1 and M2 macrophages in an ovalbumin-induced mouse model of allergic airway inflammation and asthma. After exposure to LDR (1 Gy, 1.818 mGy/h) for 24 days, mice were euthanized and the changes in the number of M1 and M2 macrophages in the bronchoalveolar lavage fluid and lung, and M2-associated cytokine levels, were assessed. LDR treatment not only restored the M2-rich microenvironment but also ameliorated asthma-related progression in a macrophage-dependent manner. In an ovalbumin-induced mouse model, LDR treatment significantly inhibited M2, but not M1, macrophage infiltration. M2-specific changes in macrophage polarization during chronic lung disease reversed the positive effects of LDR. Moreover, the levels of cytokines, including chemokine (C-C motif) ligand (CCL) 24, CCL17, transforming growth factor beta 1, and matrix metalloproteinase-9, decreased in ovalbumin-sensitized/challenged mice upon exposure to LDR. Collectively, our results indicate that LDR exposure suppressed asthmatic progression, including mucin accumulation, inflammation, and Type 2 T helper (Th2) cytokine (interleukin (IL)-4 and IL-13) production. In conclusion, LDR exposure decreased Th2 cytokine secretion in M2 macrophages, resulting in a reduction in eosinophilic inflammation in ovalbumin-sensitized/challenged mice.