RESUMEN
Although fast eating speed has been associated with cardiovascular risk factors, no studies have reported an association between fast eating speed and atherosclerosis as evaluated by carotid intima-media thickness (CIMT). Rapid glucose ingestion is known to cause glucose spikes, which may accelerate atherogenesis and increase levels of growth differentiation factor 15 (GDF-15). Therefore, GDF-15 levels may influence the association between fast eating speed and atherosclerosis. To evaluate the association between eating speed and atherosclerosis in relation to GDF-15, this cross-sectional study analyzed 742 Japanese aged 60-69 years. They were required to have normal thyroid hormone levels, because both GDF-15 levels and atherosclerosis (CIMT ≥ 1.1 mm) can be influenced by thyroid dysfunction. Participants were stratified by the median GDF-15 level. A significant positive association was observed between fast eating speed and atherosclerosis, but only among participants with a high GDF-15 level: the sex- and age-adjusted odds ratios (95% confidence intervals) were 1.95 (1.09, 3.48) in participants with a high GDF-15 level, and 0.83 (0.37, 1.88) in those with a low GDF-15 level. This association remained even after further adjustment for thyroid function and metabolic factors. Serum concentrations of GDF-15 may mediate the association between fast eating speed and atherosclerosis.
Asunto(s)
Aterosclerosis , Grosor Intima-Media Carotídeo , Factor 15 de Diferenciación de Crecimiento , Humanos , Factor 15 de Diferenciación de Crecimiento/sangre , Masculino , Femenino , Aterosclerosis/sangre , Aterosclerosis/etiología , Estudios Transversales , Anciano , Persona de Mediana Edad , Factores de RiesgoRESUMEN
The total annual effective dose has steadily decreased since the fallout of the Chernobyl Nuclear Power Plant. However, chronic internal exposure to 137Cs still persists and fluctuates in a complex and unpredictable manner. Recently, body contamination was found to primarily occur owing to the intake of forest foodstuffs that contain long-lived 137Cs. Forest foodstuffs may have up to 100 times higher concentration of cesium than does local milk and meat. The present study aimed to investigate the recent dietary habits of residents in the Zhytomyr region of Ukraine, and assess the effect of the intake of forest foodstuffs on the increase in internal radioactivity from 137Cs. We screened 1,612 participants, from July 2016 to February 2018 for internal radioactivity, using whole-body counter at Korosten Medical Center and surveyed their background and intake habits. We analyzed the association among food type, intake frequency, and internal exposure dose. The analysis revealed that nearly 90% of the participants regularly consumed one of the forest foodstuffs (mushrooms, berries, fish) or milk. Nearly 80% of the participants indicated that they consumed mushrooms or berries or both. Internal radioactivity was detected in 30% of the participants. The diet that included mushrooms exhibited the highest internal radioactivity. The lowest Bq/kg concentration was observed in the only-berry group, following the no-intake group. There was a significant correlation between the intake frequency and the magnitude of Bq/kg. Radioactivity detected in the mushroom-berry and only-mushroom group were 8.6 and 9.2 Bq/kg, respectively. The lowest and highest intake frequency showed a radioactivity of 2.4 and 7.5 Bq/kg, respectively. Radioactivity in the winter season was significantly higher than that in other seasons. In conclusion, our study revealed that internal radioactivity varies depending on the type of food, intake frequency, and season.
Asunto(s)
Agaricales , Accidente Nuclear de Chernóbil , Exposición a la Radiación , Animales , Radioisótopos de Cesio , Ucrania , FrutasRESUMEN
To maintain normal level of thyroid hormone, especially for free thyroxine (FT4), individuals with latent thyroid gland damage might have required higher thyroid stimulating hormone (TSH) than those without latent thyroid gland damage. Anti-thyroid peroxidase antibody (TPO-Ab) is a main cause of auto-immune thyroiditis, and therefore euthyroid individuals positive for TPO-Ab might have latent damage to the thyroid gland. Therefore, the association between TSH values and TPO-Ab positivity may be useful to determine the influence of latent thyroid gland damage on requirement of TSH. Furthermore, because latent damage of thyroid might elevate TSH level but not FT4 level, those associations should be observed independent from FT4. This cross-sectional study analyzed 1431 Japanese with normal ranges of free triiodothyronine (FT3) and FT4. Since TPO-Ab is associated with atherosclerosis in euthyroid individuals, cardiovascular risk factors might underlie the association between TPO-Ab and TSH values. After adjusting for FT4 and known cardiovascular risk factors, the adjusted odds ratio (95% confidence interval) of TPO-Ab positivity for logarithmic value of TSH was 1.53 (1.20, 1.95). Essentially the same association was observed when the analysis was restricted to individuals without subclinical hypothyroidism (1.54 [1.15, 2.13]). Euthyroid individuals with latent thyroid gland damage might have increased the requirement of TSH.
Asunto(s)
Hipotiroidismo , Tirotropina , Humanos , Estudios Transversales , PeroxidasasRESUMEN
Cystine and theanine (CT), an amino acid mixture, provides the substrates cysteine and glutamic acid that promote glutathione synthesis. We previously reported that CT pre-treatment significantly improved the acute survival rate and reduced acute radiation injury of the small intestine and bone marrow of rats after 5 Gy of total body X-ray irradiation. To examine the long-term effects of CT administration after irradiation, we investigated the effects of CT pre-treatment and pre- and post-treatment on the chronic survival rate and solid tumor (spleen, skin and subcutis, and thyroid) incidence after irradiation using 7-week-old male Wistar rats. CT pre-treatment of 280 mg/kg was administered orally for 5 days before 5 Gy irradiation, and CT pre- and post-treatment was administered 5 days before and 5 days after irradiation. A 0.5% carboxymethyl cellulose solution was administered as a control. The chronic survival rate of the pre-treated rats was higher than that of the control rats at 441 days after irradiation (40 vs 8.1%, P = 0.011). However, the survival rate did not significantly differ between the pre- and post-treatment and control rats at 467 days after irradiation (33.8 vs 30.2%, P = 0.792). In addition, more solid tumors, especially subcutis sarcomas, were observed in the pre-treatment rats (26.1%, 6/23) than in the control rats (4.5%, 1/22) after irradiation. Therefore, pre-administration of CT improves the chronic survival rate after irradiation; however, the occurrence of solid tumors was not suppressed.
Asunto(s)
Cistina , Neoplasias , Ratas , Masculino , Animales , Cistina/farmacología , Tasa de Supervivencia , Rayos X , Incidencia , Ratas Wistar , Glutatión/metabolismo , Irradiación Corporal TotalRESUMEN
Exposure to ionizing radiation in childhood has been recognized as a risk factor for thyroid cancer. We previously demonstrated that neonatal X-irradiation induced specific deformation of the thyroid follicles. Here, we further analyzed this model to understand the possible relationship with thyroid carcinogenesis. Wistar rats were subjected to cervical X-irradiation at different ages of 1-8 weeks old and at different doses of 1.5-12 Gy. For tumor promotion, rats were fed with an iodine-deficient diet (IDD). In cervically X-irradiated neonatal rats, the size of thyroid follicles decreased, accompanied by an increase in the number of TUNEL-positive cells. Fas and Lgals3 mRNA levels increased, while Mct8 and Lat4 expressions decreased. The co-administration of IDD induced the proliferation and the upregulation in Lgals3 expression, resulting in thyroid adenoma development at 28 weeks post-exposure. Our data demonstrated that single neonatal X-irradiation induced continuous apoptotic activity in the thyroid with the long-term alternation in Fas, Mct8, Lat4, and Lgals3 mRNA expressions. Some of these changes were similar to those induced by IDD, suggesting that neonatal X-irradiation may partially act as a thyroid tumor promoter. These radiation-induced thyroidal changes may be enhanced by the combined treatment with IDD, resulting in the early development of thyroid adenoma.
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Expresión Génica/efectos de la radiación , Glándula Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Animales , Peso Corporal , Carcinogénesis , Humanos , Recién Nacido , Tamaño de los Órganos/efectos de la radiación , Ratas , Ratas Wistar , Hormonas Tiroideas/sangre , Neoplasias de la Tiroides/genéticaRESUMEN
Childhood radiation exposure is a known thyroid cancer risk factor. This study evaluated the effects of age on radiation-induced thyroid carcinogenesis in rats irradiated with 8 Gy X-rays. We analyzed cell proliferation, cell death, DNA damage response, and autophagy-related markers in 4-week-old (4W) and 7-month-old (7M) rats and the incidence of thyroid tumors in 4W, 4-month-old (4M), and 7M rats 18 months after irradiation. Cell death and DNA damage response were increased in 4W rats compared to those in controls at 1 month post-irradiation. More Ki-67-positive cells were observed in 4W rats at 12 months post-irradiation. Thyroid tumors were confirmed in 61.9% (13/21), 63.6% (7/11), and 33.3% (2/6) of irradiated 4W, 4M, and 7M rats, respectively, compared to 0%, 14.3% (1/7), and 16.7% (1/6) in the respective nonirradiated controls. There were 29, 9, and 2 tumors in irradiated 4W, 4M, and 7M rats, respectively. The expression of several autophagy components was downregulated in the area surrounding radiation-induced thyroid carcinomas in 4W and 7M rats. LC3 and p62 expression levels decreased in radiation-induced follicular carcinoma in 4W rats. Radiosensitive cells causing thyroid tumors may be more prevalent in young rats, and abrogation of autophagy may be associated with radiation-induced thyroid carcinogenesis.
Asunto(s)
Carcinogénesis/efectos de la radiación , Neoplasias Inducidas por Radiación/epidemiología , Traumatismos Experimentales por Radiación/epidemiología , Neoplasias de la Tiroides/epidemiología , Adulto , Factores de Edad , Animales , Niño , Relación Dosis-Respuesta en la Radiación , Humanos , Incidencia , Masculino , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/patología , Traumatismos Experimentales por Radiación/etiología , Traumatismos Experimentales por Radiación/patología , Tolerancia a Radiación , Ratas , Factores de Riesgo , Glándula Tiroides/patología , Neoplasias de la Tiroides/etiología , Neoplasias de la Tiroides/patología , Rayos X/efectos adversosRESUMEN
Although the association between radiation exposure and thyroid carcinogenesis is epidemiologically evident, 'true' radiation-induced cancers cannot be identified from biological evidence of radiation-associated cases. To assess the individual risk for thyroid cancer due to radiation exposure, we aimed to identify biomarkers that are specifically altered during thyroid carcinogenesis after irradiation in a time-dependent manner in an animal model. Thyroid glands were obtained from rats (n = 175) at 6-16 months after local X-ray (0.1-4 Gy) irradiation of the neck at 7 weeks of age. The gene expression profile in thyroid glands was comprehensively analyzed using RNA microarray. Subsequently, the expression levels of the genes of interest were verified using droplet digital PCR (ddPCR). The expression level of candidate genes as biomarkers for irradiated thyroid was examined in a randomized, controlled, double-blind validation study (n = 19) using ddPCR. The incidence of thyroid cancer increased in a dose- and time-dependent manner and was 33% at 16 months after irradiation with 4 Gy. The Ki-67 labeling index in non-tumorous thyroid was significantly higher in the exposed group than in the control. Comprehensive analysis identified radiation-dependent alteration in 3329 genes. Among them, ddPCR revealed a stepwise increase in CDKN1A expression from early pre-cancerous phase in irradiated thyroid compared to that in the control. The irradiated thyroids were accurately distinguished (positive predictive value 100%, negative predictive value 69%) using 11.69 as the cut-off value for CDKN1A/ß-actin. Thus, CDKN1A expression can be used as a biomarker for irradiated thyroid glands at the pre-cancerous phase.
Asunto(s)
Carcinogénesis/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias Inducidas por Radiación/genética , Neoplasias de la Tiroides/genética , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinogénesis/patología , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Wistar , Reproducibilidad de los Resultados , Glándula Tiroides/patología , Glándula Tiroides/efectos de la radiación , Neoplasias de la Tiroides/patologíaRESUMEN
This study aims to examine the effects of cystine and theanine (CT), which increases glutathione biosynthesis, on the survival rate and acute radiation injury of the small intestine and bone marrow using a rat model. CT pre-treatment (280 mg/kg for 5 days) significantly improved weight loss and survival rate of rats as compared with the control group after 5 Gy. CT pre-treatment significantly increased the rate of mucosa and crypt length, and decreased the number of apoptotic cells, TUNEL and cleaved caspase-3 positive cells, while increasing the number of mitotic cells and Ki-67 positive cells in jejunal crypts and villi compared to control rats post-irradiation. CT also suppressed bone marrow cell loss and reduced the number of apoptotic cells in bone marrow. These results suggest a protective effect of CT pre-treatment for acute injury after irradiation through apoptosis inhibition and increased proliferative activity in jejunal crypt cells and bone marrow cells.
Asunto(s)
Cistina/uso terapéutico , Glutamatos/uso terapéutico , Traumatismos por Radiación/tratamiento farmacológico , Protectores contra Radiación/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Yeyuno/efectos de los fármacos , Yeyuno/patología , Masculino , Traumatismos por Radiación/patología , Ratas Wistar , Irradiación Corporal Total/efectos adversosRESUMEN
Exposure to ionized radiation in childhood has been recognized as a risk factor for the development of thyroid cancer and possibly for other thyroid disorders. However, the effects of neonatal radiation exposure on thyroid morphology and functions have never been explored despite its potential importance. One-week-old male Wistar rats were subjected to cervical X-irradiation at 6 and 12 Gy. Animals were examined at the ages of 2, 8 and 18 weeks old. For comparison, 8-week-old rats were cervically X-irradiated at the same doses. Thyroid histology was examined by computer-assisted microscopy to measure areas of colloid and epithelium of thyroid follicles as well as epithelial heights. In rats that received cervical X-irradiation at 1 week old, the colloid size of thyroid follicles decreased at the age of 8 weeks old in a radiation-dose dependent manner. This morphological change was persistently found at 18 weeks old. There were no significant differences in serum total T3 or T4 levels among the groups. Serum TSH levels increased significantly in 8-week-old rats neonatally X-irradiated. Thyroglobulin (Tg) mRNA and protein expressions were significantly decreased in the neonatally-irradiated group while thyroid peroxidase mRNA express increased at 18 weeks old. None of these changes were observed in the rats X-irradiated at 8 weeks old. In conclusion, our results clearly demonstrated that neonatal rat thyroid was sensitive to ionized radiation, developing specific morphological changes characterized by smaller thyroid follicles along with changes in serum TSH levels and Tg expressions in the thyroid tissue.
Asunto(s)
Yoduro Peroxidasa/efectos de la radiación , Tiroglobulina/efectos de la radiación , Glándula Tiroides/efectos de la radiación , Tirotropina/efectos de la radiación , Tiroxina/efectos de la radiación , Triyodotironina/efectos de la radiación , Rayos X , Factores de Edad , Animales , Animales Recién Nacidos , Western Blotting , Relación Dosis-Respuesta en la Radiación , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Masculino , Cuello , ARN Mensajero/metabolismo , ARN Mensajero/efectos de la radiación , Dosis de Radiación , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tiroglobulina/genética , Tiroglobulina/metabolismo , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Tirotropina/metabolismo , Tiroxina/metabolismo , Triyodotironina/metabolismoRESUMEN
Autophagy is a catabolic process that involves the degradation of cellular components through the lysosomal machinery, relocating nutrients from unnecessary processes to more pivotal processes required for survival. It has been reported that systemic disruption of the Atg5 or Atg7 gene, a component of autophagy, is lethal and that its tissue-specific disruption causes tissue degeneration in several organs. However, the functional significance of autophagy in the thyroid glands remains unknown. Our preliminary data imply the possible involvement of dysfunctional autophagy in radiation-induced thyroid carcinogenesis. Therefore, we evaluated the effect of Atg5 gene knockout (KO) on thyroid morphology and function. To this end, Atg5flox/flox mice were crossed with TPO-Cre mice, yielding the thyroid follicular epithelial cell (thyrocyte)âspecific ATG5-deficient mice (Atg5thyr-KO/KO). Atg5 gene KO was confirmed by a lack of ATG5 expression, and disruption of autophagy was demonstrated by a decrease in microtubule-associated protein 1 light chain 3-II puncta and an increase in p62. Atg5thyr-KO/KO mice were born normally, and thyroid morphology, thyroid weights, and serum T4 and TSH levels were almost normal at 4 months. However, at 8 and 12 months, a decrease in the number of thyrocytes and an increase in TUNEL+-thyrocytes were observed in Atg5thyr-KO/KO mice even though thyroid function was still normal. The number of irregularly shaped (gourd-shaped) follicles was also increased. Excess oxidative stress was indicated by increased 8-hydroxy-2'-deoxyguanosine and 53BP1 foci in Atg5thyr-KO/KO mice. These data demonstrate that thyrocytes gradually undergo degradation/cell death in the absence of basal levels of autophagy, indicating that autophagy is critical for the quality control of thyrocytes.
Asunto(s)
Autofagia/fisiología , Células Epiteliales Tiroideas/patología , 8-Hidroxi-2'-Desoxicoguanosina/análisis , Animales , Proteína 5 Relacionada con la Autofagia/fisiología , Muerte Celular , Células Epiteliales/patología , Ratones , Ratones Noqueados , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Radiation doses received by Hiroshima and Nagasaki atomic bomb survivors has been evaluated from data related only to external exposure because there was no reliable evidence for internal exposure in atomic bomb victims. However, we assumed that the contribution of internal exposure cannot be ruled out. METHODS: Autoradiography was carried out with the 70-year old paraffin-embedded specimens taken from Nagasaki atomic bomb victims who died within 5 months after the bombing. After exposure to photo emulsion for 6 months alpha-tracks were revealed in the specimens. We confirmed the alpha-tracks were emitted from deposited plutonium (Pu) in reference to the track length of the 8.787 MeV alpha-particle of thorium series from Polonium-212. Radioactivity concentration of Pu was obtained by counting alpha-tracks. The absorbed dose of each cell nucleus penetrated by an alpha-particle was estimated by calculating the absorbed energy from the particle. RESULTS: Using old paraffin embedded sections processed about 70 years ago, we demonstrated for the first time that conditions in the aftermath of the bombing led to internal exposure to alpha-particles emitted from Pu, the fissile material of the Nagasaki atomic bomb. Dose rate of internal exposure was higher in the victims exposed outdoors than those indoors. Radioactivity concentration was relatively uniform among organs examined in a victim. CONCLUSION: Pu was deposited in the bodies of the Nagasaki A-bomb victims presumably via various routes. Organ dose from Pu of the Nagasaki A-bomb victims studied was during their surviving period, which is lower compared with external exposure. However, the impact to the individual cell nucleus by a single alpha-particle might not be negligible, It would be meaningful; to analyze the relationship of the impact of internal exposure at the cellular level and organ dose. The 70-year old pathological specimens utilized in our study are an invaluable source for understanding internal radiation exposure and are crucial in elucidating experimentally unreproducible phenomena.
RESUMEN
Bioengineered lungs consisting of a decellularized lung scaffold that is repopulated with a patient's own cells could provide desperately needed donor organs in the future. This approach has been tested in rats, and has been partially explored in porcine and human lungs. However, existing bioengineered lungs are fragile, in part because of their immature vascular structure. Herein, we report the application of adipose-derived stem/stromal cells (ASCs) for engineering the pulmonary vasculature in a decellularized rat lung scaffold. We found that pre-seeded ASCs differentiated into pericytes and stabilized the endothelial cell (EC) monolayer in nascent pulmonary vessels, thereby contributing to EC survival in the regenerated lungs. The ASC-mediated stabilization of the ECs clearly reduced vascular permeability and suppressed alveolar hemorrhage in an orthotopic transplant model for up to 3 h after extubation. Fibroblast growth factor 9, a mesenchyme-targeting growth factor, enhanced ASC differentiation into pericytes but overstimulated their proliferation, causing a partial obstruction of the vasculature in the regenerated lung. ASCs may therefore provide a promising cell source for vascular regeneration in bioengineered lungs, though additional work is needed to optimize the growth factor or hormone milieu for organ culture.
Asunto(s)
Adipocitos/citología , Células Endoteliales/citología , Trasplante de Pulmón/métodos , Pulmón/citología , Células del Estroma/citología , Adipocitos/metabolismo , Animales , Bioingeniería/métodos , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Células Endoteliales/metabolismo , Células HEK293 , Humanos , Pulmón/irrigación sanguínea , Pulmón/fisiología , Masculino , Pericitos/citología , Pericitos/metabolismo , Arteria Pulmonar/citología , Ratas Endogámicas F344 , Regeneración , Células del Estroma/metabolismo , PorcinosRESUMEN
Exposure to ionizing radiation during childhood is a well-known risk factor for thyroid cancer. Our study evaluated the effect of age on the radiosensitivity of rat thyroid glands. Four-week-old (4W), 7 -week-old (7W), and 8-month-old (8M) male Wistar rats were exposed to 8 Gy of whole-body X-ray irradiation. Thyroids were removed 3-72 h after irradiation, and non-irradiated thyroids served as controls. Ki67-positivity and p53 binding protein 1 (53BP1) focus formation (a DNA damage response) were evaluated via immunohistochemistry. Amounts of proteins involved in DNA damage response (p53, p53 phosphorylated at serine 15, p21), apoptosis (cleaved caspase-3), and autophagy (LC3, p62) were determined via western blotting. mRNA levels of 84 key autophagy-related genes were quantified using polymerase chain reaction arrays. Ki67-positive cells in 4W (with high proliferative activity) and 7W thyroids significantly decreased in number post-irradiation. The number of 53BP1 foci and amount of p53 phosphorylated at serine 15 increased 3 h after irradiation, regardless of age. No increase in apoptosis or in the levels of p53, p21 or cleaved caspase-3 was detected for any ages. Levels of LC3-II and p62 increased in irradiated 4W but not 8M thyroids, whereas expression of several autophagy-related genes was higher in 4W than 8M irradiated thyroids. Irradiation increased the expression of genes encoding pro-apoptotic proteins in both 4W and 8M thyroids. In summary, no apoptosis or p53 accumulation was noted, despite the expression of some pro-apoptotic genes in immature and adult thyroids. Irradiation induced autophagy in immature, but not in adult, rat thyroids.
Asunto(s)
Envejecimiento/fisiología , Proteínas Reguladoras de la Apoptosis/metabolismo , Tolerancia a Radiación/fisiología , Radiación Ionizante , Glándula Tiroides/fisiología , Glándula Tiroides/efectos de la radiación , Animales , Autofagia/fisiología , Autofagia/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Masculino , Dosis de Radiación , Ratas , Ratas Wistar , Glándula Tiroides/citología , Irradiación Corporal TotalRESUMEN
A high dose of ionizing external radiation damage to the skin and soft tissue results in changes in function as well as in the general body condition. Once radiation surpasses the tissue safety or survival level, progressive alteration in the damaged tissue results in tissue loss and then flap loss. Local expression and action of stem cells or local growth factors in the irradiated tissue is mitigated, and external administration is sought to investigate the possibility of skin and soft tissue survival after an elevating flap. Basic fibroblast growth factor (bFGF) is primarily considered as a potent angiogenic growth factor. In burns, resurfacing with a dermal component is required, and bFGF stimulates wound healing and enhances human skin-derived mesenchymal stem cells under serum-free conditions in a dose-dependent manner. Thirty-five male, 4- to 8-week-old CLAWN miniature pigs received radiation exposure to assess the effectiveness of bFGF in terms of the progressive clinical course relevant to human skin and soft tissue. At 2 weeks following 10-Gy irradiation, tissue was preserved in the group receiving subcutaneous placement of a round-type tissue expander and bFGF. The expander plus bFGF group demonstrated significantly greater dermo-epidermal proliferation than the radiation alone, radiation plus bFGF, or expander plus radiation plus vehicle-solution groups, and new blood vessel formation was significantly increased in the expander tissue with bFGF after irradiation (p < 0.01). Electron microscopy revealed that tissue with expander and bFGF maintained more stable skin adnexae with preserved intact epidermis and dermis. Thus, bFGF improved and maintained the tissue viability after immediate irradiation in the skin and soft tissue.
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Factor 2 de Crecimiento de Fibroblastos/farmacología , Traumatismos Experimentales por Radiación/patología , Piel/patología , Células Madre/patología , Colgajos Quirúrgicos/patología , Cicatrización de Heridas , Animales , Apoptosis , Inmunohistoquímica , Masculino , Microscopía Electrónica , Dosis de Radiación , Piel/efectos de la radiación , Células Madre/efectos de la radiación , Porcinos , Cicatrización de Heridas/efectos de la radiaciónRESUMEN
We previously reported that the apoptosis index in jejunal crypt cells after X irradiation was greater in spontaneously hypertensive rats than in Wistar-Kyoto rats. Moreover, these same cells showed a suppression of apoptosis when reserpine was administered to induce sympathetic dysfunction in spontaneously hypertensive rats or Wistar-Kyoto rats. Whether the hyperfunction of the sympathetic nervous system is involved in the high susceptibility of the jejunal crypt cells to radiation-induced apoptosis was the subject of this study. The effect of norepinephrine (NE) on cell survival was examined using the colony formation assay after X-ray irradiation of rat ileal epithelial cells (IEC-18). The addition of 1 µM NE decreased the surviving fraction of cells irradiated with 6 Gy from 37% to 8%. The radiosensitivity of IEC-18 cells was enhanced by the addition of 1 µM of NE. The irradiation and treatment with NE also resulted in an increased cellular apoptotic rate. These results showing enhanced radiosensitivity of rat ileal epithelial cells by NE suggest that NE may be one of the factors which aggravate acute radiation injury in the intestine.
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Mucosa Intestinal/fisiología , Norepinefrina/farmacología , Tolerancia a Radiación/fisiología , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Células Cultivadas , Relación Dosis-Respuesta en la Radiación , Íleon/efectos de los fármacos , Íleon/fisiología , Íleon/efectos de la radiación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de la radiación , Dosis de Radiación , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Ratas , Ratas Endogámicas WKYRESUMEN
The effect of basic fibroblast growth factor (bFGF) was studied in radiation-induced apoptosis in rat jejunal crypt cells. Six-week-old male Wistar rats were administered 4 mg/kg bFGF intraperitoneally 25 h before receiving 8 Gy whole-body X rays. The jejunum was removed for analysis from time 0 to 120 h after irradiation. Villus length in control rats declined steadily until 72 h, while in bFGF-treated rats the villi were longer than in the controls until 48 h. Crypt lengths were similar to villi. bFGF treatment increased Ki-67-positive cells in the jejunal crypt at 0, 24 and 48 h. The treatment with bFGF reduced the number of apoptotic cells per jejunal crypt to 23% and 10% of the control values at 3 and 6 h, respectively, and increased numbers of mitotic cells significantly at 48 and 72 h. bFGF decreased the levels of TP53, CDKN1A, Puma and Cleaved caspase 3 at 3 h as detected by Western blot analyses. Our results suggest that bFGF protected against acute radiation-induced injury by suppressing the crypt apoptotic cells including the stem cells and promoted crypt cell proliferation. The inhibition of apoptosis thus might be related to suppression of the TP53 pathway.
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Apoptosis/efectos de la radiación , Factor 2 de Crecimiento de Fibroblastos/farmacología , Intestino Delgado/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Western Blotting , Caspasa 3/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Intestino Delgado/citología , Intestino Delgado/metabolismo , Intestino Delgado/efectos de la radiación , Masculino , Proteínas Proto-Oncogénicas/metabolismo , Ratas , Ratas WistarRESUMEN
Epidermal cells are the first cells to be exposed to environmental genotoxic agents such as ultraviolet and ionizing radiations, which induce DNA double strand breaks (DSB) and activate DNA damage response (DDR) to maintain genomic integrity. Defective DDR can result in genomic instability (GIN) which is considered to be a central aspect of any carcinogenic process. P53-binding protein 1 (53BP1) belongs to a family of evolutionarily conserved DDR proteins. Because 53BP1 molecules localize at the sites of DSB and rapidly form nuclear foci, the presence of 53BP1 nuclear foci can be considered as a cytological marker for endogenous DSB reflecting GIN. The levels of GIN were analyzed by immunofluorescence studies of 53BP1 in 56 skin tumors that included 20 seborrheic keratosis, eight actinic keratosis, nine Bowen's disease, nine squamous cell carcinoma, and 10 basal cell carcinoma. This study demonstrated a number of nuclear 53BP1 foci in human skin tumorigenesis, suggesting a constitutive activation of DDR in skin cancer cells. Because actinic keratosis showed a high DDR type of 53BP1 immunoreactivity, GIN seems to be induced at the precancerous stage. Furthermore, invasive cancers exhibited a high level of intense, abnormal 53BP1 nuclear staining with nuclear accumulation of p53, suggesting a disruption of DDR leading to a high level of GIN in cancer cells. The results of this study suggest that GIN has a crucial role in the progression of skin carcinogenesis. The detection of 53BP1 expression by immunofluorescence can be a useful histological marker to estimate the malignant potential of human skin tumors.
Asunto(s)
Inestabilidad Genómica , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Cutáneas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Núcleo Celular/metabolismo , Epidermis/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/análisis , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/genética , Proteína 1 de Unión al Supresor Tumoral P53RESUMEN
Polaprezinc, an anti-ulcer drug, is a chelate compound consisting of zinc and L-carnosine. Polaprezinc has been shown to prevent gastric mucosal injury. The anti ulcer effects of polaprezinc have been ascribed to its antioxidative property. The effect of polaprezinc on ionizing radiation-induced apoptosis was studied in the jejunal epithelial crypt cells of rats. Seven-to eight week-old Wistar rats, which were treated with 100 mg/kg of polaprezinc orally 1h before irradiation or 2% carboxymethyl cellulose sodium in controls, were exposed to whole body X-ray irradiation at 2 Gy. The number of apoptotic cells per jejunum crypt was counted in haematoxylin and eosin stained sections at 0-6 h after irradiation. TUNEL positive cells and immunopositive cells for active caspase-3 per crypt were also counted. Accumulation of p53, p21(WAF1/CIP1) and Bax expression in the jejunum after irradiation were examined by Western blot analyses. Polaprezinc treatment given prior to radiation resulted in a significant reduction in numbers of apoptotic cells, TUNEL positive cells and active caspase-3 immunopositive cells in jejunal crypt cells. Polaprezinc treatment resulted in decreases of p53 accumulation, p21(WAF1/CIP1) and Bax expression after irradiation. Polaprezinc has a protective effect against ionizing radiation induced apoptosis in rat jejunal crypt cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Carnosina/análogos & derivados , Yeyuno/citología , Yeyuno/fisiología , Compuestos Organometálicos/administración & dosificación , Animales , Carnosina/administración & dosificación , Células Cultivadas , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Yeyuno/efectos de los fármacos , Yeyuno/efectos de la radiación , Masculino , Dosis de Radiación , Protectores contra Radiación/administración & dosificación , Ratas , Ratas Wistar , Compuestos de Zinc/administración & dosificaciónRESUMEN
We postulated that nuclear dust within the lamina propria beneath the basement membrane of the epithelium in colonic mucosa is a form of apoptotic epithelial cells and that its expression triggers dextran sulfate sodium-induced colitis. The aim was to determine the origin of nuclear dust and to explore the correlation between nuclear dust expression and clinicopathologic parameters of colitis. Rats were treated with 3% dextran sulfate sodium. Cells showing double positive staining with cytokeratin and TdT-mediated uUTP-biotin nick-end labeling technique were apoptotic cells derived from epithelial cells. Nuclear dust expression on day 5 correlated with bloody stools and a decrease of mitotic colonic cells just before ulceration. Examination of cultures under light and fluorescent microscopy showed that dextran sulfate sodium caused early apoptosis and late apoptosis or necrosis. Our results suggest that interventions directed toward the apoptotic process may be beneficial in the treatment of ulcerative colitis.
Asunto(s)
Apoptosis , Membrana Basal/patología , Colitis/patología , Colon/patología , Mucosa Intestinal/patología , Animales , Apoptosis/efectos de los fármacos , Membrana Basal/efectos de los fármacos , Células Cultivadas , Colitis/inducido químicamente , Colon/efectos de los fármacos , Sulfato de Dextran , Modelos Animales de Enfermedad , Mucosa Intestinal/efectos de los fármacos , Masculino , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/patología , Ratas , Ratas WistarRESUMEN
Defective DNA damage response (DDR) can result in genomic instability (GIN) and lead to the transformation into cancer. P53-binding protein 1 (53BP1) belongs to a family of evolutionarily conserved DDR proteins. Because 53BP1 molecules localize at the sites of DNA double strand breaks (DSBs) and rapidly form nuclear foci, the presence of 53BP1 foci can be considered as a cytologic marker for endogenous DSBs reflecting GIN. Although it has been proposed that GIN has a crucial role in the progression of thyroid neoplasms, the significance of GIN during thyroid tumorigenesis remains unclear, particularly in patients. We analyzed, therefore, the level of GIN, as detected with immunofluorescence of 53BP1, in 40 cases of resected thyroid tissues. This study demonstrated a number of nuclear 53BP1 foci in thyroid cancers, suggesting a constitutive activation of DDR in thyroid cancer cells. Because follicular adenoma also showed a few 53BP1 nuclear foci, GIN might be induced at a precancerous stage of thyroid tumorigenesis. Furthermore, high-grade thyroid cancers prominently exhibited an intense and heterogeneous nuclear staining of 53BP1 immunoreactivity, which was also observed in radiation-associated cancers and in mouse colonic crypts as a delayed response to a high dose ionizing radiation, suggesting increased GIN with progression of cancer. Thus, the present study demonstrated a difference in the staining pattern of 53BP1 during thyroid carcinogenesis. We propose that immunofluorescence analysis of 53BP1 expression can be a useful tool to estimate the level of GIN and, simultaneously, the malignant potency of human thyroid tumors.