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CTRP6, a member of the C1q/TNF-related protein (CTRP) family, has gained increasing scientific interest because of its regulatory role in tumor progression. Previous studies have shown that CTRP6 is closely involved in regulating various pathophysiological processes, including glucose and lipid metabolism, cell proliferation, apoptosis, and inflammation. To date, CTRP6 has been identified as related to eight different malignancies, including lung cancer, oral cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, renal cancer, and ovarian cancer. CTRP6 is reported to be associated with tumor progression by activating a series of related signal networks. This review article mainly discusses the biochemistry and pleiotropic pathophysiological functions of CTRP6 as a new molecular mediator in carcinogenesis, hoping that the information summarized herein could make a modest contribution to the development of novel cancer treatments in the future.
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Background and Objectives: To compare the oncological and functional outcomes of brachytherapy (BT) and radical prostatectomy (RP) in patients with localized prostate cancer (PCa). Materials and Methods: We retrospectively analyzed data from 557 patients with localized PCa who were treated with BT (n = 245) or RP (n = 312) at Northern Jiangsu People's Hospital between January 2012 and December 2017. Biochemical relapse-free survival (bRFS) and cancer-specific survival (CSS) were compared by treatment modality. Multivariate Cox regression analysis was used to evaluate bRFS. Health-related quality of life (HRQoL) was measured using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Results: The BT group was older and had a higher initial PSA (iPSA). The 5-year bRFS was 82.9% in the BT group versus 80.1% in the RP group (p = 0.570). The 5-year CSS was 96.4% in the BT group versus 96.8% in the RP group (p = 0.967). Based on multivariate Cox regression analysis, Gleason score ≥ 8 was the main independent prognostic factor for bRFS. Regarding the HRQoL, compared with the baseline, both treatments produced a significant decrease in different aspects of HRQoL at 3, 6, and 12 months after treatment. Patients in the BT group had lower HRQoL with regard to urinary irritation/obstruction and bowel function or bother, while patients in the RP group had lower HRQoL concerning urinary incontinence and sexual function or bother. There was no significant difference in HRQoL aspects between the two groups after follow-up for 2 years compared with the baseline. Conclusions: BT provides equivalent oncological control outcomes in terms of bRFS and CSS for patients with localized PCa compared with RP. Gleason score ≥ 8 was the main independent prognostic factor for bRFS. BT had better HRQoL compared with RP, except for urinary irritation/obstruction and bowel function or bother, but returned to baseline after 2 years.
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Braquiterapia , Neoplasias da Próstata , Masculino , Humanos , Braquiterapia/efeitos adversos , Antígeno Prostático Específico , Qualidade de Vida , Estudos Retrospectivos , Prostatectomia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgiaRESUMO
Environmental pollution often releases multiple contaminants resulting in as yet largely uncharacterized additive toxicities. Cadmium (Cd) is a widespread pollutant that induces nephrotoxicity in animal models and humans. However, the combined effect of Cd in causing nephrotoxicity with 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a typical congener of polybrominated diphenyl ethers (PBDEs), has not been evaluated and mechanisms are not completely clear. Here, we applied transcriptome sequencing analysis to investigate the combined toxicity of Cd and BDE-47 in the renal tubular epithelial cell lines HKCs. Cd or BDE-47 exposure decreased cell viability in a dose-dependent manner, and exhibited cell swelling and rounding similar to necrosis, which was exacerbated by co-exposure. Transcriptomic analysis revealed 2191, 1331 and 3787 differentially-expressed genes following treatment with Cd, BDE-47 and co-exposure, respectively. Interestingly, functional annotation and enrichment analyses showed involvement of pathways for oxidative stress, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and inflammatory cell death for all three treatments. Examination of indices of mitochondrial function and oxidative stress in HKC cells showed that the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and intracellular calcium ion concentration [Ca2+]i were elevated, while superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) were decreased. The ratio of apoptotic and necrotic cells and intracellular lactate dehydrogenase (LDH) release were increased by Cd or BDE-47 exposure, and was aggravated by co-exposure, and was attenuated by ROS scavenger N-Acetyl-L-cysteine (NAC). NLRP3 inflammasome and pyroptosis pathway-related genes of NLRP3, adaptor molecule apoptosis-associated speck-like protein (ASC), caspase-1, interleukin-18 (IL-18) and IL-1ß were elevated, while gasdermin D (GSDMD) was down-regulated, and protein levels of NLRP3, cleaved caspase-1 and cleaved GSDMD were increased, most of which were relieved by NAC. Our data demonstrate that exposure to Cd and BDE-47 induces mitochondrial dysfunction and triggers NLRP3 inflammasome and GSDMD-dependent pyroptosis leading to nephrotoxicity, and co-exposure exacerbates this effect, which could be attenuated by inhibiting ROS. This study provides a further mechanistic understanding of kidney damage, and co-exposure impact is worthy of concern and should be considered to improve the accuracy of environmental health assessment.
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Éteres Difenil Halogenados , Inflamassomos , Acetilcisteína/farmacologia , Animais , Cádmio/toxicidade , Caspase 1/metabolismo , Células Epiteliais , Éter/metabolismo , Éter/farmacologia , Éteres Difenil Halogenados/metabolismo , Éteres Difenil Halogenados/toxicidade , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Espécies Reativas de Oxigênio/metabolismo , TranscriptomaRESUMO
ABSTRACT: Calcium (Ca) and magnesium (Mg), which play an important role in several cellular processes, is essential for normal development of the skeleton and maintenance of tissue homeostasis. Deficiency of these elements might delay bone fracture recovery or accelerates bone loss. We aimed to examine whether supplementation of trace element (TE) promotes fracture healing in accidentally fracturing adults by involvement of inflammatory mechanism.A short-term follow-up in clinic was performed. Totally, 117 subjects diagnosed with multiple fractures by traffic accidents were recruited in this study. Serum Ca and Mg levels were measured by inductively coupled plasma atomic emission spectrophotometry. Short-term changes such as serum C-reactive protein, interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha in normal treatment and TE supplement groups were detected by enzyme-linked immunosorbent assay. Student t test and the Spearman correlation were performed to analyze the data.Significantly negative correlations between Ca (râ=â0.7032; Pâ<â.001) and Mg (râ=â0.2719; Pâ<â.05) and injury severity score were observed. Serum Ca and Mg were significantly increased at Day 5, 7, and 9 following TE supplements. After treatment, serum C-reactive protein, IL-1ß, IL-6, and tumor necrosis factor alpha were significantly reduced whereas cytokine levels of the TE supplement group were found to be lower than that of the normal treatment group after Day 3.These findings suggest that Ca and Mg levels are associated with the injury severity of multiple fractures, and the supplement could reduce the inflammation, which may be beneficial for the bone recovery and disease process.
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Cálcio/sangue , Citocinas/sangue , Fraturas Ósseas , Fraturas Múltiplas , Magnésio/sangue , Acidentes de Trânsito , Adulto , Proteína C-Reativa/análise , Cálcio/administração & dosagem , Feminino , Seguimentos , Humanos , Escala de Gravidade do Ferimento , Interleucina-6/sangue , Magnésio/administração & dosagem , Masculino , Pessoa de Meia-Idade , Espectrofotometria Atômica , Fator de Necrose Tumoral alfa/sangueRESUMO
Background: Acute kidney injury (AKI) is the most common major complication of cardiac surgery field. The purpose of this study is to investigate the association between acute kidney injury and the prognoses of cardiac surgery patients in the Medical Information Mart for Intensive Care III (MIMIC-III) database. Methods: Clinical data were extracted from the MIMIC-III database. Adult (≥18 years) cardiac surgery patients in the database were enrolled. Multivariable logistic regression analyses were employed to assess the associations between acute kidney injury (AKI) comorbidity and 30-day mortality, 90-day mortality and hospital mortality. Different adjusting models were used to adjust for potential confounders. Results: A total of 6,002 patients were involved, among which 485 patients (8.08%) had comorbid AKI. Patients with AKI were at higher risks of prolonged ICU stay, hospital mortality, 90-day mortality (all P < 0.001), and 30-day mortality (P = 0.008). AKI was a risk factor for hospital mortality [Model 1, OR (95% CI) = 2.50 (1.45-4.33); Model 2, OR (95% CI) = 2.44 (1.48-4.02)], 30-day mortality [Model 1, OR (95% CI) = 1.84 (1.05-3.24); Model 2, OR (95% CI) = 1.96 (1.13-3.22)] and 90-day mortality [Model 1, OR (95% CI) = 2.05 (1.37-3.01); Model 2, OR (95% CI) = 2.76 (1.93-3.94)]. Higher hospital mortality, 30-day mortality and 90-day mortality was observed in higher KDIGO grade for cardiac surgery patients with AKI (all P < 0.05). Conclusion: Comorbid AKI increased the risk of hospital mortality, 30-day mortality, and 90-day mortality of cardiac surgery patients in the MIMIC-III database.
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Cadmium (Cd) exposure can exert an impact on carcinogenicity of breast cancer, however, the mechanism is not fully understood in triple-negative breast cancer (TNBC). We performed a TNBC MDA-MB-231 cell model and assessed the toxic effect of Cd exposure (0, 10, 20, 50, 60, 80 µM). Cd reduced cell viability in a time- and dose-dependent manner, followed by cell cycle arrest in S phase with alterations of cyclin 1A1, cyclin 1D1 and CDK2. Lactate dehydrogenase (LDH) release, apoptosis and pyroptosis were increased, which were relieved by z-VAD. Elevated ROS and NLRP3, caspase-1, IL-1ß and IL-18 were detected, which was attenuated by N-acetylcysteine. Increased bax and decreased caspase-8, caspase-9 and caspase-3 were found. gasdermin E (GSDME) was activated with cleavage of GSDME-NT, which was retarded by z-VAD. Additionally, p38 MAPK signaling pathway was activated. Our data demonstrate GSDME-activated pyroptosis in Cd toxicity, implying a potential impact on TNBC.
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Cádmio/toxicidade , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Tetrabromodiphenyl ether (BDE-47) is widely used as commercial flame retardants that can be released into the environment and finally enter human body through the food chain. It has been identified to generate neurotoxicity, but little is known about auditory damage and the underlying mechanism following BDE-47 exposure. This study aimed to assess the cell viability with BDE-47 concentration ranging from 0 to 150 µM in mouse organ of Corti-derived cell lines (HEI-OC1). Aryl hydrocarbon receptor (AhR) as an environmental sensor, reactive oxygen species (ROS), NLRP3 inflammasome and p38 MAPK pathways were detected. Results: (1) BDE-47 inhibited the viability in a time- and dose-dependent way in HEI-OC1 cells. Cell cycle was arrested in G1 phase by BDE-47; (2) Elevated intracellular ROS, LDH levels and necrosis were found, which was alleviated by pretreatment with ROS scavenger N-acetylcysteine (NAC); (3) AhR plays an essential role in ligand-regulated transcription factor activation by exogenous environmental compounds. We found increased expression of AhR and decreased downstream targets of CYP 1A1 and CYP 1B1 in BDE-47-treated HEI-OC1 cells, which was reversed by the AhR antagonist CH-223191 for 2 h before BDE-47 exposure. No significant change was detected in CYP 2B; (4) Enhanced expressions of NLRP3 and caspase-1 were induced by BDE-47, with up-regulations of both pro-inflammatory factors for IL-1ß, IL-6 and TNF-α, and anti-inflammatory factors for IL-4, IL-10 and IL-13, but down-regulation for IL-1α; (5) Additionally, the p38 MAPK signaling pathway was activated with increased phosphorylation levels of MKK/3/6, p38 MAPK and NF-kB. Overall, our findings illustrate a role of AhR in ROS-induced necrosis of cochlear hair cells by BDE-47 exposure, in which NLRP3 inflammasome and p38 MAPK signaling pathways are activated. The current study first elucidates the sense of hearing damage induced by BDE-47, and cell-specific or mixture exposures in vivo or human studies are needed to confirm this association.
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Retardadores de Chama/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Inflamassomos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Necrose/induzido quimicamente , Necrose/metabolismo , Necrose/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
RATIONALE: Dysgerminoma is a rare malignant tumor of the ovary, more frequently occurring in young women. The main signs of pseudo-Meigs syndrome (PMS) are ascites and hydrothorax accompanying benign or malignant ovarian tumors (no fibroma or fibroma-like tumor). PATIENT CONCERNS: A 19-year-old woman with fever and chest tightness for 2âdays. DIAGNOSES: Pectoral-abdominal computed tomography (CT) scan and contrast-enhanced magnetic resonance imaging revealed a large amount of right pleural effusion, a small amount of ascites, and a huge abdominopelvic mass measuring about 29.2cmâ×â11.8cmâ×â8.4âcm in the left ovary. The result of hydrothorax examination was consistent with the diagnosis of exudative pleural effusion. In addition, Rivalta-test showed a positive result and lactate dehydrogenase was elevated. The histopathological diagnosis was a giant germ cell tumor, which was consistent with dysgerminoma in terms of both morphology and immunophenotype. Based on these findings, a diagnosis of malignant ovarian neoplasm with PMS was made. INTERVENTIONS: Surgical resection of the tumor was performed. OUTCOMES: The patient recovered well after operation, and the pleural effusion and abdominal ascites vanished. No recurrence was observed during the 1-year follow-up period. LESSONS: Ovarian dysgerminoma with PMS is a rare malignant tumor of the ovary, which often occurs in young women. It should be considered in differential diagnosis of patients with a pelvic mass, ascites and pleural effusion. Early diagnosis and surgical treatment are beneficial to prolonged survival.
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Ascite , Disgerminoma , Síndrome de Meigs/diagnóstico , Neoplasias Ovarianas , Ovariectomia/métodos , Derrame Pleural , Ascite/diagnóstico por imagem , Ascite/etiologia , Antígeno Ca-125/sangue , Diagnóstico Diferencial , Disgerminoma/sangue , Disgerminoma/patologia , Disgerminoma/fisiopatologia , Disgerminoma/cirurgia , Feminino , Humanos , L-Lactato Desidrogenase/sangue , Imageamento por Ressonância Magnética/métodos , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/fisiopatologia , Neoplasias Ovarianas/cirurgia , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/etiologia , Radiografia Torácica/métodos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The main cause of chronic renal allograft dysfunction (CRAD) still remains unclear. Insulin resistance (IR) may be a potential inducement, but there is insufficient evidence about this association. We aimed to establish a rat model of CRAD complicated with IR and to explore the function and pathologic changes of the renal allograft induced by IR. METHODS: F344-to-Lewis rats of CRAD were fed a high-fat diet to induce IR. They were divided into 3 groups: IR (CRAD+IR), CRAD, and control (CTL). Serum levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were measured to evaluate the renal function. The Homeostasis Model Assessment (HOMA)-IR index was detected by comparing the values of fasting serum insulin levels (FINS) with fasting blood glucose levels (FBG). The pathologic analysis was conducted by the degree of renal lesions including glomerular lesions, renal tubular lesions, hemorrhage, inflammatory cell infiltration, fibrillation, and hyperplasia of the renal interstitium. RESULTS: In the second, third, and fourth month after surgery, serum levels of Scr and BUN in the IR group were reduced more than those in the CRAD group, while they were both higher compared to the CTL group, suggesting that renal function in the CRAD group was declined. The HOMA-IR in the IR group was greater than that in the CRAD and CTL groups, showing that simple high-fat diet feeding significantly and steadily increased FINS and FBG in CRAD complicated with IR rats. Pathologic changes indicated that the CRAD rat model was successfully constructed and was still in the early-middle stages of renal lesions 4 months after surgery, yet IR presented a significant effect on CRAD. CONCLUSION: These results indicate that the stable CRAD complicated with IR rat model can be established through a high-fat diet in CRAD rats in 4 months, and IR could be an influencing factor.
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Modelos Animais de Doenças , Resistência à Insulina , Transplante de Rim , Disfunção Primária do Enxerto/complicações , Aloenxertos , Animais , Dieta Hiperlipídica/efeitos adversos , Rim/patologia , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Transplante HomólogoRESUMO
Resveratrol (RES) is a natural non-flavonoid polyphenol with cardioprotective activities, antioxidant, antiplatelet, and antiinflammatory. However, its low aqueous solubility, chemical stability, and oral bioavailability, as well as a short circulation half-life greatly limit its clinical applications. To overcome these limitations of RES, we synthesized a methoxy poly(ethylene glycol)-b-oligomerization(D, L-Leucine) (mPEG-b-O(D, L-Leu)) nanoparticle (NP) as the carrier of RES and evaluated the myocardial-protective effectiveness of this RES/NP complex in rat myocardial ischemia-reperfusion injury models. We gauged the characterization of the NP through proton nuclear magnetic resonance spectroscopy, gel permeation chromatography, transmission electron microscope, and Fourier transform infrared spectroscopy and then loaded RES on the nanocarrier by hydrophobic interactions under physiological pH to extend the release time of RES and prolong its circulation half-life. Subsequently, we used rat cardiomyocytes (H9C2 cells) and rat MI/RI model to investigate the relationship between drug composition and myocardial preservation properties. It was found that RES was encapsulated quickly and efficiently, and displayed an effectual loading-capacity and in vitro sustained-release. Anti-MI/RI effect of the RES/NP complex was found satisfactory in rat models in vivo using free RES as the control. This study suggested that NP may prove to be a potent nanocarrier to augment the pharmacotherapy of RES against MI/RI.
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Traumatismo por Reperfusão Miocárdica , Nanopartículas , Animais , Portadores de Fármacos , Miocárdio , Polietilenoglicóis , Ratos , ResveratrolRESUMO
In a large-scale radiological incident, rapid and high-throughput biodosimetry would be needed. Gene expression-based biodosimetry is a promising approach to determine the dose received after radiation exposure. We previously identified 35 candidate genes as biodosimetry markers based on a systematic review. The goal of the current study was to establish and validate a specific gene expression-based radiological biodosimetry using a panel of highly radioresponsive genes in human peripheral blood for improving the accuracy of dose estimation. Human peripheral blood samples from 30 adult donors were irradiated to 0, 0.5, 1, 2, 3, 4, 6 and 8 Gy with 60Co γ rays at a dose rate of 1 Gy/min. We examined the expression patterns of candidate genes using real-time polymerase chain reaction (qRT-PCR) at 6, 12, 24 and 48 h postirradiation. Stepwise regression analysis was employed to develop the gene expression-based dosimetry models at each time point. Samples from another 10 healthy donors (blind samples) and four total-body irradiated (TBI) patients were used to validate the radiation dosimetry models. We observed significant linear dose-response relationships of CDKN1A, BAX, MDM2, XPC, PCNA, FDXR, GDF-15, DDB2, TNFRSF10B, PHPT1, ASTN2, RPS27L, BBC3, TNFSF4, POLH, CCNG1, PPM1D and GADD45A in human peripheral blood at the various time points. However, the expression levels of these genes were affected by inter-individual variations and gender. We found that the gender-dependent regression models could explain 0.85 of variance at 24 h postirradiation and could also accurately estimate the absorbed radiation doses with dose range of 0-5 Gy, in human peripheral blood samples irradiated ex vivo and from TBI patients, respectively. This study demonstrates that developing gender-specific biodosimetry based on a panel of highly radioresponsive genes may help advance the application of gene expression signature for dose estimation in the event of a radiological accident or in clinical treatment.
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Sangue/metabolismo , Sangue/efeitos da radiação , Radiometria/métodos , Caracteres Sexuais , Transcriptoma/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Masculino , Modelos Biológicos , Fatores de TempoRESUMO
It has been demonstrated that S1P receptors affect heart ischaemia-reperfusion (IR) induced injury. However, whether S1P receptors affect IR-induced cardiac death has not been investigated. The aim of this paper is to demonstrate the role of S1P receptors in IR-induced cardiac death. Healthy adult male Sprague-Dawley rats were assigned to the following groups: non-operation control group, sham operation group, IR group, IR group pretreated with DMSO, IR group pretreated with S1P3 agonist, IR group pretreated with an antagonist of S1P3, IR group pretreated with S1P2 and S1P3 antagonists, IR group pretreated with heptanol and antagonists of S1P2/3, and IR group pretreated with Gap26 and antagonists of S1P2/3 (heptanol acts as a Cx43 uncoupler and the mimic peptide Gap26 as Cx43 blocker). The groups with S1P2 or S1P3 agonist application before reperfusion were used to assess whether these can be used for therapy of IR. The haemodynamics, electrocardiograms (ECG), infarction area, and mortality rates were recorded. Immunohistological connexin 43 (Cx43) expression in the heart was detected in each group. Blocking S1P2/3 receptors with specific antagonists resulted in an increment of IR-induced mortality, increased infarction size, redistribution of Cx43 expression, as well as affecting the heart function. The infarction size, heart function, and mortality were totally or partially restored in the S1P2, S1P3 agonist-pretreated IR group, and the heptanol/Gap26-treated S1P2/3-blocked IR group. The S1P receptor S1P2/3 and Cx43 are involved in the IR-induced cardiac death.
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Morte Súbita Cardíaca/prevenção & controle , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Peptídeos/farmacologia , Receptores de Lisoesfingolipídeo/metabolismo , Animais , Conexina 43/antagonistas & inibidores , Conexina 43/metabolismo , Morte Súbita Cardíaca/etiologia , Heptanol/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Receptores de Esfingosina-1-FosfatoRESUMO
The identification of rapid, sensitive and highthroughput biomarkers is imperative in order to identify individuals harmed by radiation accidents, and accurately evaluate the absorbed doses of radiation. DNA microarrays have previously been used to evaluate the alterations in growth/differentiation factor 15 (GDF15) gene expression in AHH1 human lymphoblastoid cells, following exposure to γrays. The present study aimed to characterize the relationship between the dose of ionizing radiation and the produced effects in GDF15 gene expression in AHH1 cells and human peripheral blood lymphocytes (HPBLs). GDF15 mRNA and protein expression levels following exposure to γrays and neutron radiation were assessed by reverse transcriptionquantitative polymerase chain reaction and western blot analysis in AHH1 cells. In addition, alterations in GDF15 gene expression in HPBLs following ex vivo irradiation were evaluated. The present results demonstrated that GDF15 mRNA and protein expression levels in AHH1 cells were significantly upregulated following exposure to γray doses ranging between 1 and 10 Gy, regardless of the dose rate. A total of 48 h following exposure to neutron radiation, a doseresponse relationship was identified in AHH1 cells at γray doses between 0.4 and 1.6 Gy. GDF15 mRNA levels in HPBLs were significantly upregulated following exposure to γray doses between 1 and 8 Gy, within 448 h following irradiation. These results suggested that significant time and dosedependent alterations in GDF15 mRNA and protein expression occur in AHH1 cells and HPBLs in the early phases following exposure to ionizing radiation. In conclusion, alterations in GDF15 gene expression may have potential as a biomarker to evaluate radiation exposure.
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Regulação da Expressão Gênica/efeitos da radiação , Fator 15 de Diferenciação de Crescimento/genética , Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Radiação Ionizante , Adulto , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Raios gama , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Masculino , Nêutrons , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Many studies have investigated exposure biomarkers for high dose radiation. However, no systematic study on which biomarkers can be used in dose estimation through premature chromosome condensation (PCC) analysis has been conducted. The present study aims to screen the high-dose radiation exposure indicator in calyculin A-induced PCC. The dose response of multiple biological endpoints, including G2/A-PCC (G2/M and M/A-PCC) index, PCC ring (PCC-R), ratio of the longest/shortest length (L/L ratio), and length and width ratio of the longest chromosome (L/B ratio), were investigated in calyculin A-induced G2/A-PCC spreads in human peripheral blood lymphocytes exposed to 0-20Gy (dose-rate of 1Gy/min) cobalt-60 gamma-rays. The G2/A-PCC index was decreased with enhanced absorbed doses of 4-20Gy gamma-rays. The G2/A PCC-R at 0-12Gy gamma-rays conformed to Poisson distribution. Three types of PCC-R were scored according to their shape and their solidity or hollowness. The frequencies of hollow PCC-R and PCC-R including or excluding solid ring in G2/A-PCC spreads were enhanced with increased doses. The length and width of the longest chromosome, as well as the length of the shortest chromosome in each G2/M-PCC or M/A-PCC spread, were measured. All L/L or L/B ratios in G2/M-PCC or M/A-PCC spread increased with enhanced doses. A blind test with two new irradiated doses was conducted to validate which biomarker could be used in dose estimation. Results showed that hollow PCC-R and PCC-R including solid ring can be utilized for accurate dose estimation, and that hollow PCC-R was optimal for practical application.
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Carcinógenos/toxicidade , Cromossomos/efeitos dos fármacos , Raios gama/efeitos adversos , Linfócitos/efeitos da radiação , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Oxazóis/toxicidade , Adulto , Células Cultivadas , Cromossomos/efeitos da radiação , Radioisótopos de Cobalto , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Toxinas Marinhas , Micronúcleos com Defeito Cromossômico/efeitos dos fármacosRESUMO
PURPOSE: To identify new ionizing radiation (IR)-sensitive genes and observe the dose-effect of gene expression alteration (GEA) induced by IR. MATERIALS AND METHODS: Microarray was used to screen the differentially expressed genes in human lymphoblastoid cells (AHH-1) using three doses of (60)Co γ-rays (0.5-8 Gy at 1 Gy/min). Given that p53-inducible gene 3 (PIG3) was consistently upregulated, the GEA of PIG3 in AHH-1 cells and human peripheral blood lymphocytes (HPBL) induced by γ-rays (1 Gy/min) was measured at messenger RNA (mRNA) and protein levels. The GEA of PIG3 in AHH-1 cells exposed to neutron radiation (californium-252, 0.073 Gy/min) was also quantified. RESULTS: PIG3 was one of the seven differentially expressed genes found in the microarray analysis. The PIG3 mRNA and protein levels in AHH-1 cells were significantly increased from 1-10 Gy of γ-rays 8-72 h or 8-168 h after exposure, respectively. The enhancement was also observed in AHH-1 cells from 0.4-1.6 Gy of neutrons 48 h post-irradiation. The PIG3 mRNA levels (mRNA copy numbers) in HPBL were significantly increased from 1-8 Gy of γ-rays within 4-24 h post-irradiation, but the highest increase in signal-to-noise responsiveness is approximately two-fold, which was less than that of AHH-1 (approximately 20-fold). CONCLUSIONS: IR can upregulate the PIG3 gene expression in AHH-1 and HPBL in the early phase after exposure; however, the IR induced expression levels of PIG3 are greater in AHH-1 than HPBL.
Assuntos
Raios gama , Regulação da Expressão Gênica/efeitos da radiação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Adulto , Linhagem Celular , Radioisótopos de Cobalto , Relação Dose-Resposta à Radiação , Humanos , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de TempoRESUMO
The present study aims to evaluate the use of the fluorescence in situ hybridization (FISH) translocation assay for retrospective dose estimation of acute accidental exposure to radiation in the past. Reciprocal translocation analysis by FISH with three whole-chromosome probes was performed on normal peripheral blood samples. Samples were irradiated with 0-5Gy (60)Co γ-rays in vitro, and dose-effect curves were established. FISH-based translocation analyses for six accident victims were then performed, and biological doses were estimated retrospectively by comparison with the dose-effect curves. Reconstructed doses by FISH were compared with estimated doses obtained by analysis of di-centrics performed soon after exposure, or with dose estimates from tooth-enamel electron paramagnetic resonance (EPR) data obtained at the same time as the FISH analysis. Follow-up FISH analyses for an adolescent victim were performed. Results showed that dose-effect curves established in the present study follow a linear-quadratic model, regardless of the background translocation frequency. Estimated doses according to two dose-effect curves for all six victims were similar. FISH dose estimations of three adult victims exposed to accidental radiation less than a decade prior to analysis (3, 6, or 7 years ago) were consistent with those estimated with tooth-enamel EPR measurements or analyses of di-centrics. Estimated doses of two other adult victims exposed to radiation over a decade prior to analysis (16 or 33 years ago) were underestimated and two to three times lower than the values obtained from analysis of di-centrics or tooth-enamel EPR. Follow-up analyses of the adolescent victim showed that doses estimated by FISH analysis decrease rapidly over time. Therefore, the accuracy of dose estimates by FISH is acceptable only when analysis is performed less than 7 years after exposure. Measurements carried out more than a decade after exposure through FISH analysis resulted in underestimation of the biological doses compared with values obtained through analysis of di-centrics and tooth-enamel EPR.
Assuntos
Hibridização in Situ Fluorescente/métodos , Doses de Radiação , Liberação Nociva de Radioativos , Adolescente , Adulto , Células Cultivadas , Relação Dose-Resposta à Radiação , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
In November 1992, a radiation accident occurred in Xinzhou, due to the collection by a farmer of an unused (60)Co source; 37 individuals were exposed to ionizing radiation. Three individuals died and the farmer's 19-weeks-pregnant wife suffered acute radiation symptoms. Conventional chromosome analysis, cytokinesis-block micronuclei (CBMN) assay and fluorescence in situ hybridization (FISH) painting with three pairs of whole chromosome probes were used to analyze chromosomal aberrations for the pregnant female and her baby during the 16 years following the accident. The yields of dicentrics and rings (dic+r) continually declined between 41 days and 16 years after the accident. The frequency of binucleated MN also decreased over time for both mother and daughter. Sixteen years after exposure, the yields of dic+r and binucleated MN decreased to normal levels, but the reciprocal translocation frequencies remained elevated, for both mother and daughter. FISH results showed a decreasing yield of translocations with time. Based on the changes in maternal translocation frequency, the daughter's dose at the time of exposure was estimated as 1.82 (1.35-2.54)Gy. This was consistent with the clinical manifestations of severe mental retardation and low IQ score. FISH-based translocation analysis can be used for follow-up studies on accidental exposure and, after correction, for retrospective dose estimation for individuals prenatally exposed to radiation.
Assuntos
Aberrações Cromossômicas/efeitos da radiação , Exposição Ambiental/efeitos adversos , Feto/efeitos da radiação , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Lesões por Radiação/diagnóstico , Adolescente , Adulto , China , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Testes para Micronúcleos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Doses de Radiação , Lesões por Radiação/etiologia , Liberação Nociva de Radioativos , SobreviventesRESUMO
Cytogenetic investigation of stable-type aberrations (translocations) was carried out with our improved methods on 28 elderly individuals in a high-background radiation area (HBRA) in China, and on 24 elderly individuals in a control area (CA). The level of radiation in HBRA is 3 to 5 times higher than in CA. The mean frequencies of translocations per 1,000 cells in HBRA and CA were 12.4 +/- 5.3 and 10.0 +/- 3.8, respectively. No significant difference was found in the frequencies between HBRA and CA (P>0.05, Mann-Whitney U test). When elderly individuals in HBRA and CA were classified into four subgroups of HBRA nonsmokers, HBRA smokers, CA nonsmokers, and CA smokers, a significant difference was found in the frequencies between CA smokers and CA nonsmokers (P<0.05, Mann-Whitney U test). Furthermore a tendency of difference (a near T-value of 0.05 level) was found in a comparison of HBRA smokers vs. CA nonsmokers. The present results indicate that the elevated level of natural radiation in HBRA plays a less significant part than smoking in bringing about the induction rate of stable-type aberrations (translocations) in those areas.