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1.
J Radiat Res ; 65(2): 177-186, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38155365

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive joint inflammation, resulting in cartilage destruction and bone erosion. It was reported that low-dose radiation modulates immune disease. Here, we investigated whether low-dose whole-body irradiation has preventive and therapeutic effects in collagen-induced RA (CIA) mouse models. Fractionated low-dose irradiation (0.05 Gy/fraction, total doses of 0.1, 0.5 or 0.8 Gy) was administered either concurrently with CIA induction by Type II collagen immunization (preventive) or after CIA development (therapeutic). The severity of CIA was monitored using two clinical parameters, paw swelling and redness. We also measured total Immunoglobulin G (IgG) and inflammatory cytokines (interleukine (IL)-6, IL-1ß and tumor necrosis factor-alpha (TNF-α)) in the serum by enzyme-linked immunosorbent assay, and we evaluated histological changes in the ankle joints by immunohistochemistry and hematoxylin and eosin staining. Low-dose irradiation reduced CIA clinical scores by up to 41% in the preventive model and by 28% in the therapeutic model, while irradiation in the preventive model reduced the typical CIA incidence rate from 82 to 56%. In addition, low-dose irradiation in the preventive model decreased total IgG by up to 23% and decreased IL-1ß and TNF-α by 69 and 67%, and in the therapeutic model, decreased total IgG by up to 35% and decreased IL-1ß and IL-6 by 59 and 42% with statistical significance (P < 0.01, 0.05 and 0.001). Our findings demonstrate that low-dose radiation has preventive and therapeutic anti-inflammatory effects against CIA by controlling the immune response, suggesting that low-dose radiation may represent an alternative therapy for RA, a chronic degenerative immune disease.


Assuntos
Artrite Experimental , Artrite Reumatoide , Camundongos , Animais , Fator de Necrose Tumoral alfa , Irradiação Corporal Total , Artrite Experimental/radioterapia , Artrite Experimental/tratamento farmacológico , Citocinas , Artrite Reumatoide/radioterapia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Interleucina-6 , Colágeno , Imunoglobulina G/efeitos adversos
2.
Cancers (Basel) ; 12(5)2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32365904

RESUMO

Low-dose irradiation (LDI) has recently been shown to have various beneficial effects on human health, such as on cellular metabolic activities, DNA repair, antioxidant activity, homeostasis potency, and immune activation. Although studies on the immunogenic effects of LDI are rapidly accumulating, clinical trials for cancer treatment are considered premature owing to the lack of available preclinical results and protocols. Here, we aim to investigate anti-tumor and anti-metastatic effects of whole-body LDI in several tumor-bearing mouse models. Mice were exposed to single or fractionated whole-body LDI prior to tumor transplantation, and tumor growth and metastatic potential were determined, along with analysis of immune cell populations and expression of epithelial-mesenchymal transition (EMT) markers. Whole-body fractionated-LDI decreased tumor development and lung metastasis not only by infiltration of CD4+, CD8+ T-cells, and dendritic cells (DCs) but also by attenuating EMT. Moreover, a combination of whole-body LDI with localized high-dose radiation therapy reduced the non-irradiated abscopal tumor growth and increased infiltration of effector T cells and DCs. Therefore, whole-body LDI in combination with high-dose radiation therapy could be a potential therapeutic strategy for treating cancer.

3.
J Dermatol Sci ; 96(2): 81-89, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704228

RESUMO

BACKGROUND: Burn injuries are devastating traumas that functionally affect a variety of organ systems. As intensive inflammatory responses induced by burns can lead to multiple organ failures and impaired skin regeneration increases risk of infectious complex, multimodal therapeutic approaches are needed. OBJECTIVES: To investigate the role of low dose radiation (LDR) treatment for regulation of excessive inflammation and wound healing after burn injury. METHODS: Mouse burn model was established by generating third-degree burn injury in dorsal skin and local LDR less than 100 mGy was delivered to the mice. After 3 or 12 days after burn injury, systemic inflammation in liver, lung, spleen, and kidney and skin wound healing were assessed. For investigation of molecular mechanisms, HaCaT keratinocytes were administrated with serum from mice with burn injury and alteration of viability and cornification biomarkers are assessed. RESULTS: In a mouse burn model, expression of proinflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, were downregulated by LDR in major organs and wound healing capacity was increased by LDR. In skin tissue, we observed the alleviation of reactive oxygen species generation and increased antioxidant gene expression by LDR. In addition, we found that treatment of serum from mice with burn injury and LDR increased proliferation and cornification in HaCaT cells through activation of focal adhesion kinase signaling pathway. CONCLUSION: LDR could reduce proinflammatory signaling pathway and increase skin wound healing after burn injury. Therefore, the present study suggested LDR as a novel treatment for burn injury patients.


Assuntos
Queimaduras/metabolismo , Queimaduras/radioterapia , Inflamação/radioterapia , Cicatrização/efeitos da radiação , Animais , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Queratinócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Doses de Radiação , Transdução de Sinais , Pele/patologia , Pele/efeitos da radiação
4.
Sci Rep ; 9(1): 16079, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31695078

RESUMO

The prevalence of allergies has increased over the last four decades. In allergic reactions, mast cells induce a hypersensitive immune response to a substance that is normally harmless. Ionizing radiation has different biological effects depending on the dose and dose rate. In this study, we investigated whether low-dose irradiation before (preventative effect) or after (therapeutic effect) an antigen-antibody reaction has an anti-allergic effect. To test this, we activated rat basophilic leukemia (RBL-2H3) mast cells with anti-2,4-dinitrophenyl IgE (antibody) and 2,4-dinitrophenyl human serum albumin, which served as an antigen. To test for both the potential of a preventative effect and a therapeutic effect, we irradiated mast cells both before and after mast cell activation, and we measured mediator release and signaling pathway activity. Low-dose ionizing radiation suppressed mediator release from RBL-2H3 mast cells activated by the antigen-antibody reaction regardless of when the mast cells were irradiated. These results were due to the suppression of FcεRI expression. Therefore, we suggest that low-dose ionizing radiation has a preventative and therapeutic effect in allergic reactions via the FcεRI-mediated RBL-2H3 mast cell activation system.


Assuntos
Hipersensibilidade/radioterapia , Leucemia Basofílica Aguda/radioterapia , Mastócitos/efeitos da radiação , Animais , Linhagem Celular , Humanos , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Leucemia Basofílica Aguda/imunologia , Mastócitos/imunologia , Radiação Ionizante , Ratos
5.
Int J Radiat Biol ; 95(11): 1498-1506, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31287373

RESUMO

Purpose: The aim of this study was to investigate whether low-dose ionizing radiation attenuates mast cell migration by modulating migration-associated signaling pathways and the expression of chemotactic cytokines.Materials and methods: IgE-sensitized RBL-2H3 mast cells were exposed with ionizing radiation at 0.01, 0.05, 0.1, or 0.5 Gy using a 137Cs γ-irradiator and stimulated with 2,4-dinitrophenol-human serum albumin. Cell migration was determined using a transwell assay system, F-actin distribution using Alex Fluor 488-conjugated phalloidin, expression of various signaling proteins by Western blotting, mRNA expression by RT-PCR.Results: Low-dose ionizing radiation significantly suppressed mast cell migration induced by IgE-mediated mast cell activation. Furthermore, low-dose ionizing radiation altered cell morphology, as reflected by changes in F-actin distribution, and inhibited the activation of PI3K, Btk, Rac1, and Cdc42. These effects were mediated by Nr4a2, an immune-modulating factor. Knockdown of Nr4a2 reduced mast cell migration, inhibited the PI3K and Btk signaling pathways, and reduced expression of the chemotactic cytokine monocyte chemoattractant protein-1 (MCP-1). We further demonstrated that direct blockade of MCP-1 using neutralizing antibodies inhibits mast cell migration.Conclusion: Low-dose ionizing radiation inhibits mast cell migration through the regulation production of MCP-1 by Nr4a2 in the activated mast cell system.


Assuntos
Movimento Celular/efeitos da radiação , Quimiocina CCL2/metabolismo , Mastócitos/efeitos da radiação , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Interferência de RNA , Actinas/metabolismo , Animais , Linhagem Celular Tumoral , Radioisótopos de Césio , Quimiotaxia , Citocinas/metabolismo , Raios gama , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Mastócitos/citologia , Faloidina/metabolismo , Ratos , Transdução de Sinais
6.
Cell Commun Signal ; 17(1): 12, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760304

RESUMO

BACKGROUND: The existence of differentiated thyroid cells is critical to respond radioactive iodide treatment strategy in thyroid cancer, and loss of the differentiated phenotype is a trademark of iodide-refractive thyroid disease. While high-dose therapy has been beneficial to several cancer patients, many studies have indicated this clinical benefit was limited to patients having BRAF mutation. BRAF-targeted paired box gene-8 (PAX8), a thyroid-specific transcription factor, generally dysregulated in BRAF-mutated thyroid cancer. METHODS: In this study, thyroid iodine-metabolizing gene levels were detected in BRAF-transformed thyroid cells after low and high dose of ionizing radiation. Also, an mRNA-targeted approach was used to figure out the underlying mechanism of low (0.01Gyx10 or 0.1Gy) and high (2Gy) radiation function on thyroid cancer cells after BRAFV600E mutation. RESULTS: Low dose radiation (LDR)-induced PAX8 upregulation restores not only BRAF-suppressive sodium/iodide symporter (NIS) expression, one of the major protein necessary for iodine uptake in healthy thyroid, on plasma membrane but also regulate other thyroid metabolizing genes levels. Importantly, LDR-induced PAX8 results in decreased cellular transformation in BRAF-mutated thyroid cells. CONCLUSION: The present findings provide evidence that LDR-induced PAX8 acts as an important regulator for suppression of thyroid carcinogenesis through novel STAT3/miR-330-5p pathway in thyroid cancers.


Assuntos
Transformação Celular Neoplásica/patologia , Transformação Celular Neoplásica/efeitos da radiação , Proteínas Proto-Oncogênicas B-raf/metabolismo , Glândula Tireoide/patologia , Glândula Tireoide/efeitos da radiação , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Hipotireoidismo/patologia , Iodo/metabolismo , Camundongos Mutantes , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Mutação/genética , Fator de Transcrição PAX8/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Biol Open ; 8(2)2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30670376

RESUMO

Ionizing radiation is widely used in medicine and is valuable in both the diagnosis and treatment of many diseases. However, its health effects are ambiguous. Here, we report that low-dose ionizing radiation has beneficial effects in human amyloid-ß42 (Aß42)-expressing Drosophila Alzheimer's disease (AD) models. Ionizing radiation at a dose of 0.05 Gy suppressed AD-like phenotypes, including developmental defects and locomotive dysfunction, but did not alter the decreased survival rates and longevity of Aß42-expressing flies. The same dose of γ-irradiation reduced Aß42-induced cell death in Drosophila AD models through downregulation of head involution defective (hid), which encodes a protein that activates caspases. However, 4 Gy of γ-irradiation increased Aß42-induced cell death without modulating pro-apoptotic genes grim, reaper and hid The AKT signaling pathway, which was suppressed in Drosophila AD models, was activated by either 0.05 or 4 Gy γ-irradiation. Interestingly, p38 mitogen-activated protein-kinase (MAPK) activity was inhibited by exposure to 0.05 Gy γ-irradiation but enhanced by exposure to 4 Gy in Aß42-expressing flies. In addition, overexpression of phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, or a null mutant of AKT strongly suppressed the beneficial effects of low-dose ionizing radiation in Aß42-expressing flies. These results indicate that low-dose ionizing radiation suppresses Aß42-induced cell death through regulation of the AKT and p38 MAPK signaling pathways, suggesting that low-dose ionizing radiation has hormetic effects on the pathogenesis of Aß42-associated AD.

8.
Mol Ther ; 27(2): 342-354, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30424954

RESUMO

Radiotherapy has been a central part in curing non-small cell lung cancer (NSCLC). However, it is possible that not all of the tumor cells are destroyed by radiation; therefore, it is important to effectively control residual tumor cells that could become aggressive and resistant to radiotherapy. In this study, we aimed to investigate the molecular mechanism of decreased NSCLC radioresistance by low-dose radiation (LDR) pretreatment. The results indicated that miR-30a and miR-30b, which effectively inhibited plasminogen activator inhibitor-1 (PAI-1), were overexpressed by treatment of LDR to NSCLC cells. Phosphorylation of Akt and ERK, the downstream survival signals of PAI-1, was decreased by PAI-1 inhibition. Reduced cell survival and epithelial-mesenchymal transition by PAI-1 inhibition were confirmed in NSCLC cells. Moreover, in vivo orthotopic xenograft mouse models with 7C1 nanoparticles to deliver miRNAs showed that tumor growth and aggressiveness were efficiently decreased by LDR treatment followed by radiotherapy. Taken together, the present study suggested that PAI-1, whose expression is regulated by LDR, was critical for controlling surviving tumor cells after radiotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , MicroRNAs/metabolismo , Células A549 , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/genética , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Nanopartículas/química , Reação em Cadeia da Polimerase em Tempo Real , Cicatrização/genética , Cicatrização/fisiologia
9.
J Immunotoxicol ; 15(1): 137-146, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30686136

RESUMO

Immune cells are known as the most sensitive tissue for ionizing radiation. Numerous reports relating with the effect of low-dose ionizing radiation (LDIR) on immune activities showed that LDIR can induce immune-potentiation via modulating the activity of B-, T-, and NK cells, or macrophages, whereas high-dose radiation induces genome-wide apoptotic/necrotic tissue injury and immune suppression. Generally, CD4+ T-cells play pivotal roles in immune systems via cytokines and cell-surface molecules to activate other types of immune cells to eliminate the pathogen. In spite of the significance of CD4+ T-cells in the immune system, mechanism of how LDIR regulates CD4+ T-cell gene expression is poorly investigated. Thus, RNA-Seq and Gene-Set Enrichment Analysis (GSEA) analysis were done with low-dose irradiated (γ-radiation, 50 mGy, 204 mGy/h)/anti-CD3/CD28-stimulated CD4+ T-cells to explore the LDIR-specific regulation of CD4+ T-cell gene expression. The results indicated that the genes related to mRNA translation processes, mitochondrial function, cell cycle regulation, and cytokine induction were upregulated in irradiated cells. Moreover, this study showed that the expression of T-helper cell Type 1 (TH1) or type 2 (TH2) cytokine genes, such as those for interferon (IFN)-γ, interleukin (IL)-4, and IL-5 were increased by at least 1.4-fold in acute (204 mGy/h) or chronic (10 mGy/h) low-dose (10 or 50 mGy) irradiated/anti-CD3/CD28 stimulated CD4+ T-cells, whereas the T-regulatory (Treg) cell cytokine gene, transforming growth factor (TGF)-ß was decreased. Overall, these findings demonstrated that LDIR could cause an upregulation of selected immune product genes and, in turn, might modulate the activity of CD4+ T-cells undergoing activation via an impact on cytokine gene regulation.


Assuntos
Mitocôndrias/fisiologia , Radiação Ionizante , Linfócitos T Reguladores/fisiologia , Células Th1/fisiologia , Células Th2/fisiologia , Animais , Antígenos CD4/metabolismo , Ciclo Celular/genética , Células Cultivadas , Citocinas/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos da radiação , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Biossíntese de Proteínas/genética , Análise de Sequência de RNA , Linfócitos T Reguladores/efeitos da radiação , Células Th1/efeitos da radiação , Células Th2/efeitos dos fármacos
10.
Int J Oncol ; 51(5): 1583-1589, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29048635

RESUMO

Focal adhesion kinase 1 (FAK1) is known to promote tumor progression and metastasis by controlling cell movement, invasion, survival and the epithelial-to-mesenchymal transition in the tumor microenvironment. As recent reports imply that FAK1 is highly associated with tumor cell development and malignancy, the inhibition of FAK1 activity could be an effective therapeutic approach for inhibiting the growth and metastasis of tumor cells. In this study, we aimed to determine the effect of a novel synthetic FAK1 inhibitor 2-[2-(2-methoxy-4-morpholin-4-yl-phenylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-N-methyl-benzamide, (MPAP) on lung cancer cells. MPAP suppressed cancer cell proliferation and the phosphorylation of FAK1. Combined treatment with MPAP and irradiation (IR) showed enhanced suppression of cancer cell proliferation in wild-type p53 cells and more intense suppression in p53-null cells. In addition, the combination treatment effectively induced G1 cell cycle arrest in a p53-independent manner. In an in vivo tumor xenograft mouse model, treatment with both MPAP and IR reduced tumor growth more than the treatment with IR or MPAP alone. Overall, these data demonstrate that the radiosensitizing effect of MPAP is mediated by the regulation of retinoblastoma protein (RB) phosphorylation in a p53-independent manner.


Assuntos
Quinase 1 de Adesão Focal/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Benzamidas/administração & dosagem , Benzamidas/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Quinase 1 de Adesão Focal/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Radiação , Tolerância a Radiação/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int J Radiat Biol ; 93(11): 1207-1216, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28880706

RESUMO

PURPOSE: The aim of this study was to explore the potential for radiation-specific signaling of various LDIR-induced effects in human B-lymphoblast IM-9 cells. MATERIALS AND METHODS: Human lymphoblast IM-9 cells were exposed to ionizing radiation at 0.1 and 2 Gy using a 137Cs γ-irradiator at a dose rate of 0.8 Gy/min. Cell viability and DNA fragmentation were determined using MTT assay and TUNEL assay at 24 h after irradiation. Profiling of protein phosphorylation by radiation was identified using a phospho-antibody array at 4 h after irradiation and Dataset of the profiling was analyzed by IPA. RESULTS: Cell survival and apoptotic signaling were not affected by 0.1 Gy of radiation, whereas 2 Gy induced cellular damage. The analysis of low-dose ionizing radiation (LDIR) or high-dose ionizing radiation (HDIR)-specific responses by IPA generated different results. Various cell maintenance functions were only apparent following the analysis of increased protein phosphorylation by LDIR, whereas several cancer formation- and development-related functions were only detected following the analysis of increased protein phosphorylation by HDIR. CONCLUSIONS: The LDIR-induced protein phosphorylation patterns might be involved in various cell survival responses or cellular maintenance functions, which provide important insight into our understanding of the different effects of LDIR and HDIR.


Assuntos
Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Fosfoproteínas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Humanos , Linfócitos/citologia , Tolerância a Radiação/efeitos da radiação , Transdução de Sinais/efeitos da radiação
12.
Toxicol Appl Pharmacol ; 333: 17-25, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28818514

RESUMO

Although favorable immune responses to low-dose irradiation (LDI) have been observed in normal mice, i.e., a hormesis effect, little is known about the effects of LDI in infectious diseases. In this study, we examined the effects of LDI on mice with sepsis, a severe and often lethal hyperinflammatory response to bacteria. Female C57BL/6 mice were whole-body irradiated with 10cGy 48h before Escherichia coli infection, and survival, bacterial clearance, cytokines, and antioxidants were quantified. LDI pretreatment significantly increased survival from 46.7% in control mice to 75% in mice with sepsis. The bacterial burden was significantly lower in the blood, spleen, and kidney of LDI-treated mice than in those of control septic mice. The levels of pro-inflammatory cytokines, e.g., IL-1ß and IL-6, as well as anti-inflammatory IL-10 were markedly reduced in pre-LDI septic mice. Nitric oxide production by peritoneal macrophages was also reduced in pre-LDI septic mice. Immune cells in the spleen increased and Nrf2 and HO-1 were induced in pre-LDI septic mice. LDI stimulates the immune response and minimizes lethality in septic mice via enhanced bacterial clearance and reduced initial proinflammatory responses.


Assuntos
Infecções por Escherichia coli/radioterapia , Sepse/radioterapia , Irradiação Corporal Total , Animais , Contagem de Colônia Microbiana , Citocinas/sangue , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/sangue , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Feminino , Rim/microbiologia , Rim/efeitos da radiação , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Células RAW 264.7 , Sepse/sangue , Sepse/imunologia , Sepse/microbiologia , Baço/microbiologia , Baço/efeitos da radiação
13.
Int J Radiat Biol ; 93(11): 1197-1206, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28681635

RESUMO

PURPOSE: Low-dose radiation has various biological effects such as adaptive responses, low-dose hypersensitivity, as well as beneficial effects. However, little is known about the particular proteins involved in these effects. Here, we sought to identify low-dose radiation-responsive phosphoproteins in normal fibroblast cells. MATERIALS AND METHODS: We assessed genomic instability and proliferation of fibroblast cells after γ-irradiation by γ-H2AX foci and micronucleus formation analyses and BrdU incorporation assay, respectively. We screened fibroblast cells 8 h after low-dose (0.05 Gy) γ-irradiation using Phospho Explorer Antibody Microarray and validated two differentially expressed phosphoproteins using Western blotting. RESULTS: Cell proliferation proceeded normally in the absence of genomic instability after low-dose γ-irradiation. Phospho antibody microarray analysis and Western blotting revealed increased expression of two phosphoproteins, phospho-NFκB (Ser536) and phospho-P70S6K (Ser418), 8 h after low-dose radiation. CONCLUSIONS: Our findings suggest that low-dose radiation of normal fibroblast cells activates the expression of phospho-NFκB (Ser536) and phospho-P70S6K (Ser418) in the absence of genomic instability. Therefore, these proteins may be involved in DNA damage repair processes.


Assuntos
Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Instabilidade Genômica/efeitos da radiação , Fosfoproteínas/metabolismo , Proliferação de Células/efeitos da radiação , Dano ao DNA , Reparo do DNA/efeitos da radiação , Relação Dose-Resposta à Radiação , Fibroblastos/citologia , Raios gama/efeitos adversos , Regulação da Expressão Gênica/efeitos da radiação , Humanos , NF-kappa B/metabolismo , Tolerância a Radiação/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Fatores de Tempo
14.
Sci Rep ; 7: 43361, 2017 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-28240233

RESUMO

Breast cancer is a widely distributed type of cancer in women worldwide, and tumor relapse is the major cause of breast cancer death. In breast cancers, the acquisition of metastatic ability, which is responsible for tumor relapse and poor clinical outcomes, has been linked to the acquisition of the epithelial-mesenchymal transition (EMT) program and self-renewal traits (CSCs) via various signaling pathways. These phenomena confer resistance during current therapies, thus creating a major hurdle in radiotherapy/chemotherapy. The role of very low doses of radiation (LDR) in the context of EMT has not yet to be thoroughly explored. Here, we report that a 0.1 Gy radiation dose reduces cancer progression by deactivating the JAK1/STAT3 pathway. Furthermore, LDR exposure also reduces sphere formation and inhibits the self-renewal ability of breast cancer cells, resulting in an attenuated CD44+/CD24- population. Additionally, in vivo findings support our data, providing evidence that LDR is a promising option for future treatment strategies to prevent cancer metastasis in breast cancer cases.


Assuntos
Neoplasias da Mama/radioterapia , Transição Epitelial-Mesenquimal/efeitos da radiação , Raios gama/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Janus Quinase 1/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos da radiação , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Relação Dose-Resposta à Radiação , Feminino , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Plasmídeos/química , Plasmídeos/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Transfecção , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Radiat Res ; 58(3): 329-340, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28122968

RESUMO

Ionizing radiation causes biological damage that leads to severe health effects. However, the effects and subsequent health implications caused by exposure to low-dose radiation are unclear. The objective of this study was to determine phosphoprotein profiles in normal human fibroblast cell lines in response to low-dose and high-dose γ-radiation. We examined the cellular response in MRC-5 cells 0.5 h after exposure to 0.05 or 2 Gy. Using 1318 antibodies by antibody array, we observed ≥1.3-fold increases in a number of identified phosphoproteins in cells subjected to low-dose (0.05 Gy) and high-dose (2 Gy) radiation, suggesting that both radiation levels stimulate distinct signaling pathways. Low-dose radiation induced nucleic acid-binding transcription factor activity, developmental processes, and multicellular organismal processes. By contrast, high-dose radiation stimulated apoptotic processes, cell adhesion and regulation, and cellular organization and biogenesis. We found that phospho-BTK (Tyr550) and phospho-Gab2 (Tyr643) protein levels at 0.5 h after treatment were higher in cells subjected to low-dose radiation than in cells treated with high-dose radiation. We also determined that the phosphorylation of BTK and Gab2 in response to ionizing radiation was regulated in a dose-dependent manner in MRC-5 and NHDF cells. Our study provides new insights into the biological responses to low-dose γ-radiation and identifies potential candidate markers for monitoring exposure to low-dose ionizing radiation.


Assuntos
Biomarcadores/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos da radiação , Raios gama , Fosfoproteínas/metabolismo , Proteômica , Western Blotting , Linhagem Celular , Dano ao DNA , Relação Dose-Resposta à Radiação , Fibroblastos/metabolismo , Humanos , Análise Serial de Proteínas , Reprodutibilidade dos Testes
16.
Eur J Cell Biol ; 95(6-7): 219-27, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27107455

RESUMO

Accumulating evidence suggests the potential for radiation therapy to generate antitumor immune responses against tumor cells by inducing immunogenic cell death and phenotypic changes. We recently found that ionizing radiation upregulated karyopherin α2 (KPNA2) in HT-29 colorectal tumor cells using quantitative proteomic analysis. To determine whether this increased KPNA2 could function as a damage-associated molecular pattern to induce antitumor immune responses, mouse bone-marrow-derived dendritic cells (BMDCs) were treated with KPNA2. KPNA2 enhanced the surface expression of CD40, CD54, CD80, CD86, and MHC class I/II on BMDCs. DCs treated with KPNA2 exhibited increased secretion of pro-inflammatory cytokines such as IL-1ß, IL-6, IL-12, IL-23, and TNF-α. Co-culture of CD4(+) T cells and KPNA2-treated DCs resulted in induction of Th1/17 cytokines (IFN-γ and IL-17) and reduction of TGF-ß production. Moreover, KPNA2-treated DCs were capable of increasing granzyme B and perforin expression in cytotoxic T lymphocytes. These results demonstrated that radiation-induced dying colorectal cancer cells released considerable amounts of KPNA2 that induce the maturation and activation of DCs for synergistic antitumor effect of radiation.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/radioterapia , Células Dendríticas/imunologia , Proteínas Nucleares/imunologia , alfa Carioferinas/imunologia , Animais , Morte Celular/fisiologia , Morte Celular/efeitos da radiação , Diferenciação Celular/fisiologia , Diferenciação Celular/efeitos da radiação , Proliferação de Células/fisiologia , Proliferação de Células/efeitos da radiação , Neoplasias Colorretais/patologia , Células Dendríticas/efeitos da radiação , Feminino , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos da radiação , Regulação para Cima/efeitos da radiação , alfa Carioferinas/metabolismo
17.
Int J Radiat Oncol Biol Phys ; 94(5): 1207-18, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27026320

RESUMO

PURPOSE: To determine how low-dose ionizing radiation (LDIR) regulates B lympho-proliferation and its molecular mechanism related with Ikaros, transcription factor. METHODS AND MATERIALS: Splenocytes and IM-9 cells were uniformly irradiated with various doses of a (137)Cs γ-source, and cell proliferation was analyzed. To determine the LDIR-specific phosphorylation of Ikaros, immunoprecipitation and Western blot analysis were performed. To investigate the physiologic function of LDIR-mediatied Ikaros phosphorylation, Ikaros mutants at phosphorylation sites were generated, and cell cycle analysis was performed. RESULTS: First, we found that LDIR enhances B lymphoblast proliferation in an Ikaros-dependent manner. Moreover, we found that LDIR elevates the phosphorylation level of Ikaros protein. Interestingly, we showed that CK2 and AKT are involved in LDIR-induced Ikaros phosphorylation and capable of regulating DNA binding activity of Ikaros via specific phosphorylation. Finally, we identified LDIR-specific Ikaros phosphorylation sites at S391/S393 and showed that the Ikaros phosphorylations at these sites control Ikaros's ability to regulate G1/S cell cycle progression. CONCLUSION: Low-dose ionizing radiation specifically phosphorylates Ikaros protein at Ser 391/393 residues to regulate cell cycle progression in B lymphoblast.


Assuntos
Linfócitos B/efeitos da radiação , Caseína Quinase II/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia , Fator de Transcrição Ikaros/metabolismo , Proteínas Proto-Oncogênicas c-akt/fisiologia , Pontos de Checagem da Fase S do Ciclo Celular/fisiologia , Linfócitos B/citologia , Linfócitos B/fisiologia , Linhagem Celular , Proliferação de Células/efeitos da radiação , DNA/metabolismo , Humanos , Fator de Transcrição Ikaros/genética , Mutação , Fosforilação/genética , Fosforilação/efeitos da radiação , Doses de Radiação , Radiação Ionizante
18.
Sci Rep ; 5: 15809, 2015 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-26515758

RESUMO

Recently low dose irradiation has gained attention in the field of radiotherapy. For lack of understanding of the molecular consequences of low dose irradiation, there is much doubt concerning its risks on human beings. In this article, we report that low dose irradiation is capable of blocking the oncogenic KRAS-induced malignant transformation. To address this hypothesis, we showed that low dose irradiation, at doses of 0.1 Gray (Gy); predominantly provide defensive response against oncogenic KRAS -induced malignant transformation in human cells through the induction of antioxidants without causing cell death and acts as a critical regulator for the attenuation of reactive oxygen species (ROS). Importantly, we elucidated that knockdown of antioxidants significantly enhanced ROS generation, invasive and migratory properties and abnormal acini formation in KRAS transformed normal as well as cancer cells. Taken together, this study demonstrates that low dose irradiation reduces the KRAS induced malignant cellular transformation through diminution of ROS. This interesting phenomenon illuminates the beneficial effects of low dose irradiation, suggesting one of contributory mechanisms for reducing the oncogene induced carcinogenesis that intensify the potential use of low dose irradiation as a standard regimen.


Assuntos
Transformação Celular Neoplásica/efeitos da radiação , Raios gama , Proteínas ras/genética , Apoptose/efeitos da radiação , Catalase/antagonistas & inibidores , Catalase/genética , Catalase/metabolismo , Linhagem Celular , Movimento Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Transição Epitelial-Mesenquimal , Glutationa Peroxidase/antagonistas & inibidores , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Células MCF-7 , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas ras/metabolismo
19.
Eur J Cell Biol ; 94(12): 653-60, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26362471

RESUMO

Despite many studies of the effect of ionizing radiation, biological mechanisms of action might differ greatly depend on dose, dose rate, and cell type. This study was performed to explore the effects of low- and high-dose radiation in human immune cell lines. We examined cell sensitivity after irradiation with 0.05, 0.1, or 2Gy in two normal cell lines and three tumor cell lines. Low-dose radiation of 0.05 and 0.1Gy had no effect on cell survival in any tested cell line, with the exception of IM-9 cells, whose viability was transiently increased. However, IM-9 and C1R-sB7 cells were very sensitive to high-dose radiation-induced cell death, whereas Jurkat and JM1 cells showed moderate sensitivity, and THP-1 cells were completely resistant. This radiosensitivity was correlated with basal AKT activation, which is induced by phosphorylation. In radiosensitive IM-9 cells, priming with chronic low-dose irradiation blocked cell death induced by high-dose radiation challenge via inhibition of caspase activation and PARP cleavage. AKT phosphorylation was not altered in IM-9 cells, but ERK phosphorylation was greatly elevated immediately after chronic low-dose irradiation. Taken together, our results suggest that the different responses of normal and tumor cells to low-dose and high-dose radiation depend on AKT activation, which is regulated by protein phosphatase 2 (PP2A). In radiosensitive normal cells lacking basal AKT activity, chronic low-dose radiation increases activation of the ERK pathway, which plays an important role in the adaptive response to radiation, providing a very important insight into understanding the effects of ionizing radiation on health.


Assuntos
Adaptação Fisiológica/efeitos da radiação , Sistema de Sinalização das MAP Quinases , Linfócitos T/efeitos da radiação , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Ativação Enzimática , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tolerância a Radiação
20.
PLoS One ; 10(8): e0136394, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26317642

RESUMO

Ionizing radiation has different biological effects according to dose and dose rate. In particular, the biological effect of low-dose radiation is unclear. Low-dose whole-body gamma irradiation activates immune responses in several ways. However, the effects and mechanism of low-dose radiation on allergic responses remain poorly understood. Previously, we reported that low-dose ionizing radiation inhibits mediator release in IgE-mediated RBL-2H3 mast cell activation. In this study, to have any physiological relevance, we investigated whether low-dose radiation inhibits allergic responses in activated human mast cells (HMC-1(5C6) and LAD2 cells), mouse models of passive cutaneous anaphylaxis and the late-phase cutaneous response. High-dose radiation induced cell death, but low-dose ionizing radiation of <0.5 Gy did not induce mast cell death. Low-dose ionizing radiation that did not induce cell death significantly suppressed mediator release from human mast cells (HMC-1(5C6) and LAD2 cells) that were activated by antigen-antibody reaction. To determine the inhibitory mechanism of mediator released by low-dose ionizing radiation, we examined the phosphorylation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, and protein kinase C, as well as the intracellular free Ca2+ concentration ([Ca2+]i). The phosphorylation of signaling molecules and [Ca2+]i following stimulation of FcεRI receptors was inhibited by low dose ionizing radiation. In agreement with its in vitro effect, ionizing radiation also significantly inhibited inflammatory cells infiltration, cytokine mRNA expression (TNF-α, IL-4, IL-13), and symptoms of passive cutaneous anaphylaxis reaction and the late-phase cutaneous response in anti-dinitrophenyl IgE-sensitized mice. These results indicate that ionizing radiation inhibits both mast cell-mediated immediate- and delayed-type allergic reactions in vivo and in vitro.


Assuntos
Imunoglobulina E/imunologia , Anafilaxia Cutânea Passiva/efeitos da radiação , Radiação Ionizante , Animais , Sinalização do Cálcio , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mastócitos/imunologia , Mastócitos/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Anafilaxia Cutânea Passiva/imunologia , Fosfolipase C gama/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptores de IgE/imunologia , Quinase Syk , Quinases da Família src/metabolismo
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