RESUMO
Inflammatory markers have been associated with increased risk of several cancers, including colon, lung, breast and liver, but the evidence is inconsistent. We conducted a nested case-control study in the longitudinal cohort of atomic-bomb survivors. The study included 224 hepatocellular carcinoma (HCC) cases and 644 controls individually matched to cases on gender, age, city and time and method of serum storage, and countermatched on radiation dose. We measured C-reactive protein (CRP) and interleukin (IL)-6 using stored sera obtained within 6 years before HCC diagnosis from 188 HCC cases and 605 controls with adequate volumes of donated blood. Analyses with adjustment for hepatitis virus infection, alcohol consumption, smoking habit, body mass index (BMI) and radiation dose showed that relative risk (RR) of HCC [95% confidence interval (CI)] in the highest tertile of CRP levels was 1.94 (0.72-5.51) compared to the lowest tertile (p = 0.20). RR of HCC (95% CI) in the highest tertile of IL-6 levels was 5.12 (1.54-20.1) compared to the lowest tertile (p = 0.007). Among subjects with BMI > 25.0 kg/m(2) , a stronger association was found between a 1-standard deviation (SD) increase in log IL-6 and HCC risk compared to subjects in the middle quintile of BMI (21.3-22.9 kg/m(2) ), resulting in adjusted RR (95% CI) of 3.09 (1.78-5.81; p = 0.015). The results indicate that higher serum levels of IL-6 are associated with increased HCC risk, independently of hepatitis virus infection, lifestyle-related factors and radiation exposure. The association is especially pronounced among subjects with obesity.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Interleucina-6/sangue , Neoplasias Hepáticas/sangue , Neoplasias Induzidas por Radiação/sangue , Carcinoma Hepatocelular/complicações , Estudos de Casos e Controles , Feminino , Humanos , Estilo de Vida , Neoplasias Hepáticas/complicações , Masculino , Pessoa de Meia-Idade , Armas Nucleares , Obesidade/complicações , Fatores de Risco , SobreviventesRESUMO
We isolated ten compounds from methanolic extract of the peels of sacred lotus (Nelumbo nucifera) rhizomes which were identified as ß-sitosterol linoleate 1, ß-sitosterol 2, lupeol 3, stigmasterol 3-O-ß-D-glucoside 4, oleanolic acid 5, betulinic acid 6, pinoresinol 7, 4-hydroxybenzoic acid 8, catechin 9 and gallocatechin 10. All of the isolated compounds from the peels of sacred lotus rhizomes are reported for the first time, and were investigated for their anti-allergic activity. We found that three of them, stigmasterol 3-O-ß-D-glucoside 4, oleanolic acid 5 and pinoresinol 7, were capable of inhibiting A23187-induced degranulation in RBL-2H3 cells with IC50 values 0.18 ± 0.01 mM, 0.28 ± 0.06 mM, and 0.27 ± 0.01 mM, respectively. With an exception to 4, compounds 5 and 7 achieved the anti-allergic effect without affecting the cells viability even at higher concentrations with their selectivity indices (SI) being >5. By reducing A23187-induced degranulation, it is suggestive of a mechanism attenuation of Ca2+ elevation. Our findings suggest that, the peels of sacred lotus rhizomes would be beneficial for providing an inexpensive source for the production of bioactive compounds with anti-allergic effect.
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Two longitudinal cohort studies of Japanese atomic bomb survivors-the life span study (LSS) and the adult health study (AHS)-from the Radiation Effects Research Foundation (RERF) indicate that total body irradiation doses less than 1 Gy are associated with an increased risk of cardiovascular disease (CVD), but several questions about this association remain.In particular, the diversity of heart disease subtypes and the high prevalence of other risk factors complicate the estimates of radiation effects. Subtype-specific analyses with more reliable diagnostic criteria and measurement techniques are needed. The radiation effects on CVD risk are probably tissue-reaction (deterministic) effects, so the dose-response relationships for various subtypes of CVD may be nonlinear and therefore should be explored with several types of statistical models.Subpopulations at high risk need to be identified because effects at lower radiation doses may occur primarily in these susceptible subpopulations. Whether other CVD risk factors modify radiation effects also needs to be determined. Finally, background rates for various subtypes of CVD have historically differed substantially between Japanese and Western populations, so the generalisability to other populations needs to be examined.Cardiovascular disease mechanisms and manifestations may differ between high-dose local irradiation and low-dose total body irradiation (TBI)-microvascular damage and altered metabolism from low-dose TBI, but coronary artery atherosclerosis and thrombotic myocardial infarcts at high localised doses. For TBI, doses to organs other than the heart may be important in pathogenesis of CVD, so data on renal and liver disorders, plaque instability, microvascular damage, metabolic disorders, hypertension and various CVD biomarkers and risk factors are needed. Epidemiological, clinical and experimental studies at doses of less than 1 Gy are necessary to clarify the effects of radiation on CVD risk.
Assuntos
Doenças Cardiovasculares/mortalidade , Armas Nucleares/estatística & dados numéricos , Lesões por Radiação/mortalidade , Monitoramento de Radiação/estatística & dados numéricos , Contagem Corporal Total/estatística & dados numéricos , Adulto , Carga Corporal (Radioterapia) , Humanos , Incidência , Japão/epidemiologia , Doses de Radiação , Fatores de Risco , Taxa de Sobrevida , SobreviventesRESUMO
In regenerative medical products for clinical applications, a major concern is the risk of ruminant-derived materials developing transmissible spongiform encephalopathy (TSE) in the manufacturing process. Because of the risk of TSE causing prion disease, the raw materials derived from ruminants should be compliant with the "Standard for Biological Raw Materials" to ensure the quality and safety of pharmaceutical products. We therefore tested whether plasmid DNA could withstand four chemical reagents (Gdn-HCl, Gdn-SCN, TCA, or SDS), having referred to the report by Tateishi et al. [1], which describes how Creutzfeldt-Jakob disease pathogens can be inactivated by chemical reagents capable of producing a 7-log reduction in prion inactivation. We observed that plasmid DNA was mixed with chemical reagents and that the functionality of plasmid DNA was equivalent for both chemical and non-chemical treatment. The potency of plasmid DNA was monitored by the existence of DNA fragments and the function by which GFP proteins were produced by HEK293-cell transfected plasmid DNA. The existence of DNA fragments was detected in plasmid DNA treated by chemical reagents, except when undergoing TCA treatment. Additionally, when HEK293 cells were transfected with the plasmid DNA after chemical treatment, GFP protein was produced. These results indicate that plasmid DNA can withstand the chemical treatments for blocking prion transmission.
RESUMO
In this work, we utilized spontaneously hypertensive rats (SHR) and Wister Kyoto rats (WKY), from which the SHR was established, to evaluate the effects of whole-body acute radiation on the cardiovascular system at doses from 0 to 4 Gy. In the irradiated SHR, the systolic blood pressure (SBP) increased with increasing dose, while body weight gain decreased with increasing radiation dose. Furthermore, pathological observations of SHR demonstrated that the number of rats with cystic degeneration in the liver increased with increasing dose. The effects observed among SHR, such as increased SBP and retardation of body weight gain, appear very similar to those observed in Japanese atomic bomb survivors. In contrast, the SBP among WKY did not change relative to dose; the body weight, however, did change, as in the SHR. Therefore, the association between radiation exposure and SBP, but not between radiation exposure and retardation of body weight gain, may be affected by genetic background, as evident from strain difference. These results suggest that the SHR and WKY animal models may be useful for studying radiation effects on non-cancer diseases including circulatory diseases, chronic liver disease and developmental retardation.
Assuntos
Pressão Sanguínea/genética , Pressão Sanguínea/efeitos da radiação , Peso Corporal/genética , Peso Corporal/efeitos da radiação , Patrimônio Genético , Animais , Fígado/patologia , Fígado/efeitos da radiação , Masculino , Ratos , Ratos Endogâmicos SHRRESUMO
An aliphatic ester of hydroxysalicylic acid (6), reported for the first time from a natural source in addition to five known compounds were isolated from the fermented Carica papaya L. preparation, a commercialized functional food. The known compounds were identified as 5-hydroxymethylfurfuraldehyde (1), trans-caffeic acid (2), butyl 4-hydroxybenzoate (butylparaben) (3), lycopene (4), benzyl isothiocyanate (5). Compounds 1 and 3 were reported for the first time from Papaya fruits through this study. The new compound showed a moderate antioxidant activity and a potent hair growth stimulating activity in vitro.
Assuntos
Antioxidantes/isolamento & purificação , Carica/química , Cabelo/crescimento & desenvolvimento , Preparações de Plantas/química , Ácido Salicílico/química , Antioxidantes/farmacologia , Ésteres , Frutas/química , Cabelo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ácido Salicílico/isolamento & purificação , Ácido Salicílico/farmacologiaRESUMO
Exposure to high-doses of ionizing radiation has been reported to be associated with the risk of stroke. However, risks associated with lower dose exposures remain unclear, and there is little information available for the risk modification according to the dose-rate. There are few studies using animal models which might be able to provide complementary information on this association. In this study, the male stroke-prone spontaneously hypertensive rat (SHRSP) was used as a model animal. The rats were acutely irradiated with doses between 0 and 1.0 Gy or chronically irradiated with a cumulative dose of 0.5 or 1.0 Gy (at a dose rate of 0.05 or 0.1 Gy/day, respectively). The onset time of stroke related symptoms in SHRSP was used as an endpoint for evaluating the effects of low dose and the low dose-rate gamma-ray exposures. With respect to acute exposure, the time to the onset of stroke in the irradiated rats suggested the presence of a threshold around 0.1 Gy. For the low dose-rate chronically exposed, no significant increase in stroke symptom was observed. These findings are novel and demonstrate that the SHRSP system can be used to determine the association between the risk of stroke and radiation exposure with high sensitivity. Moreover, these studies provide important information regarding the association between the low dose and low dose-rate radiation exposure and circulatory diseases, especially stroke.
Assuntos
Radiação Ionizante , Acidente Vascular Cerebral/patologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais , Fatores de TempoRESUMO
Lung cancer is a leading cause of cancer death worldwide. Prevention could be improved by identifying susceptible individuals as well as improving understanding of interactions between genes and etiological environmental agents, including radiation exposure. The epidermal growth factor receptor (EGFR)-signaling pathway, regulating cellular radiation sensitivity, is an oncogenic cascade involved in lung cancer, especially adenocarcinoma. The cytosine adenine (CA) repeat number polymorphism in the first intron of EGFR has been shown to be inversely correlated with EGFR production. It is hypothesized that CA repeat number may modulate individual susceptibility to lung cancer. Thus, we carried out a case-cohort study within the Japanese atomic bomb (A-bomb) survivor cohort to evaluate a possible association of CA repeat polymorphism with lung cancer risk in radiation-exposed or negligibly exposed (<5 mGy) A-bomb survivors. First, by dividing study subjects into Short and Long genotypes, defined as the summed CA repeat number of two alleles < or = 37 and > or = 38, respectively, we found that the Short genotype was significantly associated with an increased risk of lung cancer, specifically adenocarcinoma, among negligibly exposed subjects. Next, we found that prior radiation exposure significantly enhanced lung cancer risk of survivors with the Long genotype, whereas the risk for the Short genotype did not show any significant increase with radiation dose, resulting in indistinguishable risks between these genotypes at a high radiation dose. Our findings imply that the EGFR pathway plays a crucial role in assessing individual susceptibility to lung adenocarcinoma in relation to radiation exposure.
Assuntos
Suscetibilidade a Doenças , Receptores ErbB/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Neoplasias Induzidas por Radiação/genética , Polimorfismo Genético , Idoso , Estudos de Coortes , Feminino , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Guerra Nuclear , Armas Nucleares , Doses de Radiação , SobreviventesRESUMO
A new lanostane-type triterpenoid, lucidumol D (1) was isolated from the fruiting bodies of Ganoderma lingzhi. Its structure was elucidated on the basis of extensive 1D- and 2D-NMR studies as well as mass spectrometry. The cytotoxicity of lucidumol D against proliferation of several cancer cells were assayed by using MTT method and the obtained result suggested selective anti-proliferative and cytotoxic effects against MCF-7, HepG2, HeLa, Caco-2, and HCT-116. In comparison to lucidumol C (2) isolated previously by our group, the structure-activity relationship indicated that carbonyl function at C-11 is necessary to enhance the cytotoxicity.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Ganoderma/química , Triterpenos/química , Triterpenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Carpóforos/química , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We identified that suppressor of cytokine signaling-3 (SOCS-3) gene was aberrantly methylated in its CpG island in three of 10 human hepatocellular carcinoma (HCC) cell lines. SOCS-3 RNA was undetectable in five of the 10 HCC cell lines including the three methylated cell lines, and a demethylating agent, 5-aza-2'-deoxycytidine, reactivated SOCS-3 expression in three cell lines tested. The DNA region where we found aberrant DNA methylation includes a signal transducers and activators of transcription (STAT) binding consensus sequence. When the DNA region was used as a promoter, DNA methylation markedly reduced promoter activity. SOCS-3 was also aberrantly methylated in six of 18 primary HCC samples. SOCS-3 expression was reduced in three of the three methylated and one of the three unmethylated primary samples examined. Restoration of SOCS-3 in cells lacking SOCS-3 expression suppressed STAT3 phosphorylation and cell growth. We found that IL-6 acted as a growth factor in HCC cells. Inhibition of SOCS-3 expression in cells whose growth was induced by IL-6 enhanced STAT3 phosphorylation and cell growth. In addition, AG490, a chemical JAK2 inhibitor, suppressed cell growth and downregulated STAT3 phosphorylation, but not FAK phosphorylation. We also found that SOCS-3 physically interacted with phosphorylated FAK and Elongin B in HCC cells. Restoration of SOCS-3 decreased FAK phosphorylation as well as FAK protein level. Inhibition of SOCS-3 expression increased FAK phosphorylation, resulting in enhancement of cell migration. These data indicate that SOCS-3 negatively regulates cell growth and cell motility by inhibiting Janus kinase (JAK)/STAT and FAK signalings in HCC cells. Thus, loss of SOCS-3 by the associated DNA methylation confers cells advantage in growth and migration.
Assuntos
Carcinoma Hepatocelular/patologia , Divisão Celular/fisiologia , Movimento Celular/fisiologia , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Inativação Gênica , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Repressoras/fisiologia , Transdução de Sinais , Transativadores/metabolismo , Fatores de Transcrição/fisiologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Fosforilação , Proteínas Repressoras/genética , Fator de Transcrição STAT1 , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina , Fatores de Transcrição/genéticaRESUMO
We have identified a novel gene encoding a pyrin domain protein of 89 amino acids that is expressed in various tissues including liver, brain, and spleen. The protein is highly homologous to the pyrin domain of apoptosis-associated speck-like protein (ASC). Therefore, we termed it ASC-like (ASCL). We found that ASCL gene was densely and frequently (80%) methylated in hepatocellular carcinoma (HCC) cell lines. In contrast, normal liver samples did not show any significant methylation. This aberrant methylation correlated well with the suppression of RNA expression. Furthermore, a demethylating agent, 5-aza-2'-deoxycytidine, reactivated the ASCL expression in the methylation-silenced cells, indicating that ASCL is silenced by the associated DNA methylation. ASCL methylation was also found in primary HCC (4 of 17 samples), although the frequency was less than that in cell lines. In addition, we found that ASC was also methylated in primary samples (6 of the 17). Interestingly, either ASCL or ASC methylation was observed in 53% (9 of the 17) of primary HCC samples. Significantly, the restoration of ASCL in the methylation-silenced cells demonstrated growth suppression in colony formation assay. This growth suppression effect of ASCL was supported by apoptotic changes observed in ASCL-transfected cells in which annexin-V binding was positive and caspase-3 was activated. Based on the methylation-silencing and the growth suppression activity, we propose that ASCL plays a significant role in the development of HCC.
Assuntos
Apoptose , Azacitidina/análogos & derivados , Carcinoma Hepatocelular/patologia , Proteínas do Citoesqueleto/genética , Metilação de DNA , Inativação Gênica , Neoplasias Hepáticas/patologia , Sequência de Aminoácidos , Anexina A5/metabolismo , Azacitidina/farmacologia , Proteínas Adaptadoras de Sinalização CARD , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Caspase 3 , Caspases/metabolismo , Proteínas do Citoesqueleto/metabolismo , Decitabina , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Proteínas/química , Pirina , Homologia de Sequência de Aminoácidos , Células Tumorais CultivadasRESUMO
We investigated whether endothelium-derived relaxing (EDRF) and hyperpolarizing factor (EDHF) is impaired in type 2 diabetic rats (Otsuka Long-Evans Tokushima Fatty (OLETF) rat) and whether the exercise training improves impaired EDRF and EDHF. Diabetic rats were divided into the sedentary and exercise-trained groups at the age of 16 weeks. Long-Evans Tokushima Otsuka (LETO) rats were used as age-matched non-diabetic controls. EDRF as well as EDHF induced by acetylcholine in the presence of indomethacine and L-nitro N-arginine was significantly attenuated in the diabetic rats, and was further impaired with age. Exercise training significantly improved it. Both insulin resistance and abdominal fat accumulation were significantly greater in the diabetic rats, compared with the non-diabetic rats, but were decreased in exercise-trained rats. Urinary NO(2) secretion was decrease in the diabetic rats at each age, and it was improved by exercise training. The results of the study indicated that exercise training prevented impairment of EDHF, as well as EDRF in type 2 diabetic rats, presumably due to improvement of hyperglycemia and insulin resistance and increase in the production of nitric oxide by exercise training.
Assuntos
Acetilcolina/farmacologia , Fatores Biológicos/fisiologia , Diabetes Mellitus Tipo 2/terapia , Terapia por Exercício , Óxido Nítrico/fisiologia , Vasodilatadores/farmacologia , Fatores Etários , Animais , Aorta Abdominal/metabolismo , Aorta Torácica/metabolismo , Glicemia/análise , Peso Corporal/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Histamina/farmacologia , Lipídeos/sangue , Masculino , Relaxamento Muscular/efeitos dos fármacos , Óxido Nítrico/urina , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos OLETF , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta1 , Resultado do TratamentoRESUMO
OBJECTIVE: The novel vaso-constricting 31-amino acid-length endothelin-1 [ET-1(1-31)] is selectively produced by human mast cell chymase via its action on big ET-1. However, the pathological role of ET-1(1-31) in atherosclerosis remains unclear. The aim of this study was to clarify vasoconstrictive response and expression of ET-1(1-31) in atherosclerotic aorta. METHODS AND RESULTS: Syrian golden hamster, was used for preparing the atherosclerotic models by the administration of a high cholesterol diet (HC), treatment with the nitric oxide synthase inhibitor (Nomega-nitro-L-arginine methylester, L-NAME) alone, or both (HC and L-NAME) for 40 weeks. Early atherosclerosis was observed in the case of HC or L-NAME alone treatments respectively and severe atherosclerosis was observed in the case of combined HC and L-NAME treatment. Vasoconstriction induced by ET-1(1-31) was not altered by the atherosclerotic changes, but the expression pattern of ET-1(1-31) was different at each stage of the atherosclerotic aorta. ET-1(1-31) was observed rarely in normal aortas or in early atherosclerotic lesions, but ET-1(1-31) expression was dramatically increased in aortic neointima and adventitia in a state of atherosclerosis with severe inflammation. CONCLUSION: ET-1(1-31) might play in a role of promoting atherosclerosis, and especially be involved in inflammatory mediation during the progression of atherosclerosis.
Assuntos
Aorta Torácica/fisiopatologia , Arteriosclerose/fisiopatologia , Endotelina-1/análogos & derivados , Endotelina-1/metabolismo , Fragmentos de Peptídeos/metabolismo , Vasoconstrição/fisiologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Pressão Sanguínea/fisiologia , Colesterol/sangue , Cricetinae , Modelos Animais de Doenças , Frequência Cardíaca/fisiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hipercolesterolemia/fisiopatologia , Masculino , Triglicerídeos/sangueRESUMO
Endothelin (ET)-1(1-31) is a novel vasoconstrictor peptide produced by human mast cell chymase, which selectively cleaves big ET-1 at the Try(31)-Gly(32) bond. We investigated the localization of ET-1(1-31) in various hamster tissues by immunohistochemistry and compared it to the distribution of ET-1(1-21). We found that the localization and amount of ET-1(1-31) were different from those of ET-1(1-21) in each tissue. ET-1(1-31)-like immunoreactivities (IR) in the heart, lung, and adrenal gland were observed in the same areas as ET-1(1-21) but were significantly weaker, suggesting that ET-1(1-31) might play a role only in mast cell/chymase-related pathological conditions in these tissues. In the liver, ET-1(1-31)-like IR was strongly detected in Kupffer cells where ET-1(1-21)-like IR was seen more weakly. In the kidney, ET-1(1-31)-like IR was slightly higher than ET-1(1-21). These results suggest that ET-1(1-31) might have physiological roles distinct from those of ET-1(1-21) in some hamster tissues.
Assuntos
Endotelina-1/análogos & derivados , Endotelina-1/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Cromatografia de Afinidade , Cromatografia Líquida de Alta Pressão , Quimases , Cricetinae , Endotelina-1/imunologia , Imunoquímica , Imuno-Histoquímica , Masculino , Mesocricetus , Fragmentos de Peptídeos/imunologia , Peptídeos/metabolismo , Serina Endopeptidases/metabolismo , Distribuição TecidualRESUMO
Human chymase converts big endothelin (ET)-1 to 31-amino acid length ET-1 {ET-1(1-31)} that also possesses a potent vasoconstrictive action. In addition, ET-1(1-31) is an intermediate peptide, which is then readily transformed to mature ET-1 by the neutral endopeptidase 24-11. To investigate the relevance of pathophysiology of ET-1(1-31) in vivo, we have developed specific sandwich-type, enzyme-linked immunosorbent assay to measure the plasma concentration of ET-1(1-31) in healthy volunteers and patients with myocardial infarction. The plasma concentrations of ET-1(1-31) in healthy volunteers were 24.8 ± 5.2 pg/ml (n=11). ET-1(1-31) concentration in plasma was elevated in patients with acute myocardial infarction, and its elevation was several times higher and lasted longer than that of ET-1. In addition, tissue concentration of ET-1(1-31) in the myocardium from a patient with acute myocardial infarction was extremely high (12729.8 ± 2617.7 pg/mg protein). These results suggest that ET-1(1-31) may play some pathological roles in the remodeling, especially in sites where inflammatory cells produced a large amount of proteases, such as myocardial infarction.
Assuntos
Endotelina-1/análise , Infarto do Miocárdio/metabolismo , Fragmentos de Peptídeos/análise , Adulto , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The mechanisms of aberrant CpG island methylation in oncogenesis are not fully characterized. In particular, little is known about the mechanisms of inhibition of CpG island methylation. Here we show that sal-like 3 (SALL3) is a novel inhibitory factor for DNA methyltransferase 3 alpha (DNMT3A). SALL3 binds to DNMT3A by a direct interaction between the double zinc finger motif of SALL3 and the PWWP domain of DNMT3A. SALL3 expression reduces DNMT3A-mediated CpG island methylation in cell culture and in vitro. CpG island methylation is enhanced in SALL3-depleted cells. Consistently, DNMT3A from SALL3-depleted cells increases methyltransferase activity in vitro. Binding of DNMT3A to chromatin is reduced or increased by SALL3 expression or depletion, respectively, accounting for the mechanism by which SALL3 inhibits DNMT3A-mediated CpG island methylation. We also show that SALL3 is inducible by BMP-4 and silenced by associated DNA methylation in hepatocellular carcinoma (HCC). Our results suggest that silencing of SALL3 results in acceleration of DNA methylation in HCC. This functional characterization of SALL3 sheds light on regulatory mechanisms for DNMT3A and provides new strategies to inhibit aberrant methylation in cancer.
Assuntos
Carcinoma Hepatocelular/enzimologia , Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/enzimologia , Fatores de Transcrição/metabolismo , Proteína Morfogenética Óssea 4/farmacologia , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Cromatina/metabolismo , Metilação de DNA/efeitos dos fármacos , DNA Metiltransferase 3A , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Hepáticas/genética , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: A link between exposure to fine particulate matter and cardiovascular events has been established. Inhaled nanoparticles are thought to pass through the lungs to reach other tissues via systemic circulation and to induce cell or tissue injuries. It was recently shown that long-term exposure to intra-tracheal dispersion of nano-sized carbon black (CB) exacerbates atherosclerotic lesions in low-density lipoprotein receptor-deficient mice. Because intra-tracheal dispersion of CB may be associated with aggregate formation and may not be an ideal method for CB exposure, whole-body inhalation exposure was used in the present study, the aim of which was to examine whether exposure of rats to nano-sized CB particles by inhalation leads to translocation of these particles into the circulation, exerting direct adverse effects on extrapulmonary tissues. METHODS AND RESULTS: Sprague-Dawley rats were exposed to a high dose of CB or filtered air for 6 h/day, 5 days a week for a total of 4 weeks. Although the presence of CB was confirmed in pulmonary macrophages, electron microscopic survey did not detect CB in other tissues including liver, spleen and aorta. CB exposure raised blood pressure levels in an exposure-time dependent manner. Levels of circulating inflammatory marker proteins, including monocyte chemoattractant protein-1, interleukin-6, and C-reactive protein, were higher in the CB-treated group than in the controls. CONCLUSION: Evidence of translocation of inhaled CB was not obtained. It is likely that inhaled nano-sized CB particles form aggregations in the lung and do not exert direct adverse effects on extrapulmonary tissues. Air-pollution-mediated cardiovascular events appear to be induced by the low-grade inflammatory response to the accumulation of aggregated nano-sized particles in the lung.
Assuntos
Inflamação/etiologia , Exposição por Inalação/efeitos adversos , Material Particulado/efeitos adversos , Animais , Transporte Biológico , Biomarcadores/sangue , Pressão Sanguínea , Nanopartículas , Ratos , Ratos Sprague-Dawley , Fuligem , Distribuição TecidualRESUMO
BACKGROUND: Nanomaterials have numerous potential benefits for society, but the potential hazards of nanomaterials on human health are poorly understood. Nanomaterials are known to pass into the circulatory system in humans, causing vascular injuries that might play a role in the development of atherosclerosis. The present study aimed to determine the effects of chronic exposure to nanomaterials on macrophage phenotype and platelet aggregation. METHODS AND RESULTS: Cultured macrophages (RAW264.7) were treated with carbon black (CB) and water-soluble fullerene (C60(OH)24) from 7 to 50 days. Individually, CB had no significant effects on RAW264.7 cell growth, whereas C60(OH)24 alone or CB and C60(OH)24 together with oxidized low-density lipoprotein (Ox-LDL) (100 microg/ml) induced cytotoxic morphological changes, such as Ox-LDL uptake-induced foam cell-like formation and decreased cell growth, in a dose-dependent manner. C60(OH)24 induced LOX-1 protein expression, pro-matrix metalloprotease-9 protein secretion, and tissue factor mRNA expression in lipid-laden macrophages. Although CB or C60(OH)24 alone did not induce platelet aggregation, C60(OH)24 facilitated adenosine diphosphate (ADP)-induced platelet aggregation. Furthermore, C60(OH)24 acted as a competitive inhibitor of ADP receptor antagonists in ADP-mediated platelet aggregation. CONCLUSIONS: The present study confirmed novel effects of nanomaterials in macrophages and platelets. These effects suggest that exposure to nanomaterials might be a risk for atherothrombotic diseases.
Assuntos
Lipoproteínas LDL/efeitos dos fármacos , Macrófagos/metabolismo , Nanoestruturas/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Animais , Aterosclerose/induzido quimicamente , Linhagem Celular , Fulerenos/efeitos adversos , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Fuligem/efeitos adversosRESUMO
BACKGROUND: Subclinical hypothyroidism, defined as high serum thyroid-stimulating hormone (TSH) levels and normal serum free-triiodothyronine (fT3) and serum free-thyroxine (fT4) levels, is a common medical problem among the elderly, but it is unclear whether it should be treated with thyroid hormone replacement therapy. METHODS AND RESULTS: A cross-sectional study of 3,607 participants in a community health survey in Suita, in the northern part of Osaka, was performed. Participants were categorized into 5 groups: normal, hyperthyroidism, hypothyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism. The association between each group and various phenotypes was examined, in relation to cardiovascular disease and metabolic syndromes. Serum TSH levels increased and fT3 and fT4 levels decreased with age. A total of 14.6% of subjects aged 70-80 years and 20.1% of subjects aged older than 80 years were classified as having subclinical hypothyroidism. Subclinical hypothyroidism was not associated with glycol-hemoglobin A1c, body mass index, pulse rate, hypertension, total cholesterol, high-density lipoprotein cholesterol or triglyceride levels or intima-media thickness. It was only associated with higher fasting blood glucose and glycol-hemoglobin A1c levels compared with euthyroidism. CONCLUSIONS: The present observation does not support the need for treatment of subclinical hypothyroidism or subclinical hyperthyroidism.
Assuntos
Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Doenças da Glândula Tireoide/metabolismo , Doenças da Glândula Tireoide/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Estudos Transversais , Feminino , Hemoglobinas Glicadas/metabolismo , Terapia de Reposição Hormonal , Humanos , Hipertireoidismo/metabolismo , Hipertireoidismo/fisiopatologia , Hipotireoidismo/metabolismo , Hipotireoidismo/fisiopatologia , Japão , Masculino , Pessoa de Meia-Idade , Fenótipo , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
BACKGROUND: Associations between exposure to particulate matter and susceptibility to cardiovascular events have been reported. Although the underlying mechanisms are not fully understood, this association seems to be particularly exaggerated in the presence of atherothrombotic risk factors. The present study was undertaken in low-density lipoprotein receptor knockout (LDLR/KO) mice to test the hypothesis that long-term exposure to a high dose of nano-sized carbon black (CB) exacerbates atherosclerotic lesions. METHODS AND RESULTS: LDLR/KO mice were subjected to a 10-week intratracheal dispersion of CB (1 mg/week) or air under a 0% or 0.51% cholesterol (Chol) diet. Development of aortic lipid-rich lesions was detected in mice under a 0.51% Chol diet with or without CB dispersion, but not in mice fed a 0% Chol diet with or without CB. Quantification of the area stained with oil red O revealed the highest percentage in CB-treated mice on a 0.51% Chol diet among the 4 groups. One-way ANOVA indicated CB-treated mice with 0.51% Chol diet had a significantly higher percentage of positive staining than vehicle-treated mice with 0.51% Chol diet (p<0.05). CONCLUSIONS: In LDLR-deficient mice under a high Chol diet, exposure to CB resulted in acceleration of development of atherosclerosis.