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In Wilson disease (WD), liver copper (Cu) excess, caused by mutations in the ATPase Cu transporting beta (ATP7B), has been extensively studied. In contrast, in the gastrointestinal tract, responsible for dietary Cu uptake, ATP7B malfunction is poorly explored. We therefore investigated gut biopsies from WD patients and compared intestines from two rodent WD models and from human ATP7B knock-out intestinal cells to their respective wild-type controls. We observed gastrointestinal (GI) inflammation in patients, rats and mice lacking ATP7B. Mitochondrial alterations and increased intestinal leakage were observed in WD rats, Atp7b-/- mice and human ATP7B KO Caco-2 cells. Proteome analyses of intestinal WD homogenates revealed profound alterations of energy and lipid metabolism. The intestinal damage in WD animals and human ATP7B KO cells did not correlate with absolute Cu elevations, but likely reflects intracellular Cu mislocalization. Importantly, Cu depletion by the high-affinity Cu chelator methanobactin (MB) restored enterocyte mitochondria, epithelial integrity, and resolved gut inflammation in WD rats and human WD enterocytes, plausibly via autophagy-related mechanisms. Thus, we report here before largely unrecognized intestinal damage in WD, occurring early on and comprising metabolic and structural tissue damage, mitochondrial dysfunction, and compromised intestinal barrier integrity and inflammation, that can be resolved by high-affinity Cu chelation treatment.
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ATPasas Transportadoras de Cobre , Cobre , Degeneración Hepatolenticular , Mucosa Intestinal , Ratones Noqueados , Degeneración Hepatolenticular/metabolismo , Degeneración Hepatolenticular/patología , Degeneración Hepatolenticular/tratamiento farmacológico , Animales , Humanos , ATPasas Transportadoras de Cobre/genética , ATPasas Transportadoras de Cobre/metabolismo , Cobre/metabolismo , Ratas , Ratones , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de los fármacos , Masculino , Células CACO-2 , Femenino , Adulto , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Intestinos/patología , Intestinos/efectos de los fármacos , Adulto JovenRESUMEN
Olfactory Schwannomas (OS) are a rare, benign tumour entity. Throughout literature, only few cases have been reported. We describe here a case of a 75-year-old female with a contrast enhanced mass lesion in the anterior fossa, who underwent a surgical removal and its histopathological analysis was consistent with a schwannoma. The description of the origin of this tumour is intriguing and enigmatic. Although rare, this type of tumour should always be included in the differential diagnosis of anterior fossa lesions. Further research on the pathogenesis and the natural course of OS is needed.
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Neurilemoma , Femenino , Humanos , Anciano , Neurilemoma/diagnóstico por imagen , Neurilemoma/cirugía , Diagnóstico Diferencial , OlfatoRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0221502.].
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PURPOSE: The MSc Radiation Biology course is a highly interdisciplinary degree program placing radiation biology at the interface between biology, medicine, and physics, as well as their associated technologies. The goal was to establish an internationally acknowledged program with diverse and heterogeneous student cohorts, who benefit from each other academically as well as culturally. We have completed a Five-Year evaluation of the program to assess our qualification profile and the further direction we want to take. MATERIALS AND METHODS: We evaluated the student cohort's data from the last 5 years regarding gender, age, and nationality as well as the highest degree before applying and career path after graduation. RESULTS: Data shows a great diversity regarding nationalty as well as undergraduate background. Cohort sizes could be increased and future prospects mainly aimed to a PhD. Measures after regular quality meetings and students' feedback led to improving the curriculum and workload, teacher's training, and changes to examination regulations. CONCLUSIONS: After 5 years, statistics show that our expectations have been met exceedingly. All graduates had excellent career opportunities reflecting the necessity of this MSc and its topics. We are continuously working on improving the program and adapting the curriculum to the requirements in radiation sciences. The future vision includes an expansion of the program as well as undergraduate education opportunities in this field.
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Radiobiología/educación , Adulto , Curriculum , Femenino , Humanos , MasculinoRESUMEN
PURPOSE: The increasing use of low-dose ionizing radiation in medicine requires a systematic study of its long-term effects on the brain, behaviour and its possible association with neurodegenerative disease vulnerability. Therefore, we analysed the long-term effects of a single low-dose irradiation exposure at 10 weeks of age compared to medium and higher doses on locomotor, emotion-related and sensorimotor behaviour in mice as well as on hippocampal glial cell populations. MATERIALS AND METHODS: We determined the influence of radiation dose (0, 0.063, 0.125 or 0.5 Gy), time post-irradiation (4, 12 and 18 months p.i.), sex and genotype (wild type versus mice with Ercc2 DNA repair gene point mutation) on behaviour. RESULTS: The high dose (0.5 Gy) had early-onset adverse effects at 4 months p.i. on sensorimotor recruitment and late-onset negative locomotor effects at 12 and 18 months p.i. Notably, the low dose (0.063 Gy) produced no early effects but subtle late-onset (18 months) protective effects on sensorimotor recruitment and exploratory behaviour. Quantification and morphological characterization of the microglial and the astrocytic cells of the dentate gyrus 24 months p.i. indicated heightened immune activity after high dose irradiation (0.125 and 0.5 Gy) while conversely, low dose (0.063 Gy) induced more neuroprotective features. CONCLUSION: This is one of the first studies demonstrating such long-term and late-onset effects on brain and behaviour after a single radiation event in adulthood.
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Conducta Animal/efectos de la radiación , Neuroglía/efectos de la radiación , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Hipocampo/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Actividad Motora/efectos de la radiación , Irradiación Corporal Total , Proteína de la Xerodermia Pigmentosa del Grupo D/genéticaRESUMEN
Tissue factor is highly expressed in sub-endothelial tissue. The extracellular allosteric disulfide bond Cys186-Cys209 of human tissue factor shows high evolutionary conservation and in vitro evidence suggests that it significantly contributes to tissue factor procoagulant activity. To investigate the role of this allosteric disulfide bond in vivo, we generated a C213G mutant tissue factor mouse by replacing Cys213 of the corresponding disulfide Cys190-Cys213 in murine tissue factor. A bleeding phenotype was prominent in homozygous C213G tissue factor mice. Pre-natal lethality of 1/3rd of homozygous offspring was observed between E9.5 and E14.5 associated with placental hemorrhages. After birth, homozygous mice suffered from bleedings in different organs and reduced survival. Homozygous C213G tissue factor male mice showed higher incidence of lung bleedings and lower survival rates than females. In both sexes, C213G mutation evoked a reduced protein expression (about 10-fold) and severely reduced pro-coagulant activity (about 1000-fold). Protein glycosylation was impaired and cell membrane exposure decreased in macrophages in vivo. Single housing of homozygous C213G tissue factor males reduced the occurrence of severe bleeding and significantly improved survival, suggesting that inter-male aggressiveness might significantly account for the sex differences. These experiments show that the tissue factor allosteric disulfide bond is of crucial importance for normal in vivo expression, post-translational processing and activity of murine tissue factor. Although C213G tissue factor mice do not display the severe embryonic lethality of tissue factor knock-out mice, their postnatal bleeding phenotype emphasizes the importance of fully functional tissue factor for hemostasis.
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Disulfuros , Tromboplastina , Animales , Femenino , Hemorragia/genética , Masculino , Ratones , Mutación , Fenotipo , Embarazo , Tromboplastina/genéticaAsunto(s)
Betacoronavirus , Anticoagulantes , Encéfalo , COVID-19 , Infecciones por Coronavirus , Humanos , Pandemias , Neumonía Viral , SARS-CoV-2RESUMEN
The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads.
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Ratones Endogámicos/genética , Fenotipo , Animales , Ratones de Colaboración Cruzada/genética , Bases de Datos Genéticas , Femenino , Estudios de Asociación Genética , Genotipo , Masculino , Ratones , Sitios de Carácter Cuantitativo , Especificidad de la EspecieRESUMEN
Glutathione peroxidase 4 (GPX4) is unique as it is the only enzyme that can prevent detrimental lipid peroxidation in vivo by reducing lipid peroxides to the respective alcohols thereby stabilizing oxidation products of unsaturated fatty acids. During reticulocyte maturation, lipid peroxidation mediated by 15-lipoxygenase in humans and rabbits and by 12/15-lipoxygenase (ALOX15) in mice was considered the initiating event for the elimination of mitochondria but is now known to occur through mitophagy. Yet, genetic ablation of the Alox15 gene in mice failed to provide evidence for this hypothesis. We designed a different genetic approach to tackle this open conundrum. Since either other lipoxygenases or non-enzymatic autooxidative mechanisms may compensate for the loss of Alox15, we asked whether ablation of Gpx4 in the hematopoietic system would result in the perturbation of reticulocyte maturation. Quantitative assessment of erythropoiesis indices in the blood, bone marrow (BM) and spleen of chimeric mice with Gpx4 ablated in hematopoietic cells revealed anemia with an increase in the fraction of erythroid precursor cells and reticulocytes. Additional dietary vitamin E depletion strongly aggravated the anemic phenotype. Despite strong extramedullary erythropoiesis reticulocytes failed to mature and accumulated large autophagosomes with engulfed mitochondria. Gpx4-deficiency in hematopoietic cells led to systemic hepatic iron overload and simultaneous severe iron demand in the erythroid system. Despite extremely high erythropoietin and erythroferrone levels in the plasma, hepcidin expression remained unchanged. Conclusively, perturbed reticulocyte maturation in response to Gpx4 loss in hematopoietic cells thus causes ineffective erythropoiesis, a phenotype partially masked by dietary vitamin E supplementation.
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Eritropoyesis , Hierro , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Reticulocitos , Vitamina E , Animales , Homeostasis , Ratones , ConejosRESUMEN
INTRODUCTION: The major stress-inducible heat shock protein 70 (Hsp70) is induced after different stress stimuli. In tumors, elevated intracellular Hsp70 levels were associated on the one hand with radio- and chemotherapy resistance and on the other hand with a favorable outcome for patients. This study was undertaken to investigate cytosolic Hsp70 (cHsp70) as a potential biomarker for progression free (PFS) and overall survival (OS) in patients with primary glioblastomas (GBM). METHODS: The cHsp70 expression in tumor tissue of 60 patients diagnosed with primary GBM was analyzed by immunohistochemistry. The cHsp70 expression was correlated to the PFS and OS of the patients. RESULTS: A high cHsp70 expression was associated with a prolonged PFS (hazard ratio = 0.374, p = 0.001) and OS (hazard ratio = 0.416, p = 0.014) in GBM patients treated according to the standard Stupp protocol with surgery, radiotherapy and temozolomide. CONCLUSIONS: These data suggest that the intracellular Hsp70 expression might serve as a prognostic marker in patients with primary GBM.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Citosol/metabolismo , Glioblastoma/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Adulto , Anciano , Neoplasias Encefálicas/patología , Supervivencia sin Enfermedad , Femenino , Glioblastoma/patología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Resultado del Tratamiento , Adulto JovenRESUMEN
Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by hemolytic anemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other observations indicate it could be a protein misfolding disease with tissue-specific differences in TPI activity. We generated a mouse model in which exchange of a conserved catalytic amino acid residue (isoleucine to valine, Ile170Val) reduces TPI specific activity without affecting the stability of the protein dimer. TPIIle170Val/Ile170Val mice exhibit an approximately 85% reduction in TPI activity consistently across all examined tissues, which is a stronger average, but more consistent, activity decline than observed in patients or symptomatic mouse models that carry structural defect mutant alleles. While monitoring protein expression levels revealed no evidence for protein instability, metabolite quantification indicated that glycolysis is affected by the active site mutation. TPIIle170Val/Ile170Val mice develop normally and show none of the disease symptoms associated with TPI deficiency. Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency.
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Anemia Hemolítica Congénita no Esferocítica/patología , Errores Innatos del Metabolismo de los Carbohidratos/patología , Dominio Catalítico/genética , Triosa-Fosfato Isomerasa/deficiencia , Triosa-Fosfato Isomerasa/genética , Anemia Hemolítica Congénita no Esferocítica/enzimología , Animales , Conducta Animal , Errores Innatos del Metabolismo de los Carbohidratos/enzimología , Modelos Animales de Enfermedad , Estabilidad de Enzimas , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Multimerización de ProteínaRESUMEN
The article Dose-responses for mortality from cerebrovascular and heart diseases in atomic bomb survivors: 1950-2003, written by Helmut Schöllnberger.
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BACKGROUND & AIMS: In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage. METHODS: Control Atp7b+/- and Wilson disease Atp7b-/- rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b-/- rats to test for therapeutic reversal of mitochondrial copper damage. RESULTS: In comparison with a normal diet, HCD feeding of Atp7b-/- rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b-/- rats, correlating with severe liver injury. Mitochondria presented with massive structural damage, increased H2O2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage. CONCLUSIONS: A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.
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Dieta , Degeneración Hepatolenticular/patología , Hígado/patología , Mitocondrias/patología , Animales , Ácidos y Sales Biliares/biosíntesis , Cobre/sangre , ATPasas Transportadoras de Cobre/metabolismo , Progresión de la Enfermedad , Hígado Graso/patología , Femenino , Hepatocitos/patología , Hepatocitos/ultraestructura , Degeneración Hepatolenticular/sangre , Inflamación/patología , Lípidos/biosíntesis , Hígado/metabolismo , Hígado/ultraestructura , Masculino , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Péptidos/farmacología , Proteoma/metabolismo , RatasRESUMEN
Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present study, we report the comprehensive analysis of a newly generated R155C VCP knock-in mouse model, which expresses the ortholog of the second most frequently occurring human pathogenic VCP mutation. Heterozygous R155C VCP knock-in mice showed decreased plasma lactate, serum albumin and total protein concentrations, platelet numbers, and liver to body weight ratios, and increased oxygen consumption and CD8+/Ly6C + T-cell fractions, but none of the typical human IBMPFD or ALS pathologies. Breeding of heterozygous mice did not yield in the generation of homozygous R155C VCP knock-in animals. Immunoblotting showed identical total VCP protein levels in human IBMPFD and murine R155C VCP knock-in tissues as compared to wild-type controls. However, while in human IBMPFD skeletal muscle tissue 70% of the total VCP mRNA was derived from the mutant allele, in R155C VCP knock-in mice only 5% and 7% mutant mRNA were detected in skeletal muscle and brain tissue, respectively. The lack of any obvious IBMPFD or ALS pathology could thus be a consequence of the very low expression of mutant VCP. We conclude that the increased and decreased fractions of the R155C mutant VCP mRNA in man and mice, respectively, are due to missense mutation-induced, divergent alterations in the biological half-life of the human and murine mutant mRNAs. Furthermore, our work suggests that therapy approaches lowering the expression of the mutant VCP mRNA below a critical threshold may ameliorate the intrinsic disease pathology.
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Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/genética , Genes Letales , Distrofia Muscular de Cinturas/genética , Mutación , Miositis por Cuerpos de Inclusión/genética , Osteítis Deformante/genética , Proteína que Contiene Valosina/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Antígenos Ly/genética , Antígenos Ly/metabolismo , Encéfalo/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Modelos Animales de Enfermedad , Femenino , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen , Heterocigoto , Humanos , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Osteítis Deformante/metabolismo , Osteítis Deformante/patología , Transducción de Señal , Especificidad de la Especie , Proteína que Contiene Valosina/metabolismoRESUMEN
Animal welfare requires the adequate housing of animals to ensure health and well-being. The application of environmental enrichment is a way to improve the well-being of laboratory animals. However, it is important to know whether these enrichment items can be incorporated in experimental mouse husbandry without creating a divide between past and future experimental results. Previous small-scale studies have been inconsistent throughout the literature, and it is not yet completely understood whether and how enrichment might endanger comparability of results of scientific experiments. Here, we measured the effect on means and variability of 164 physiological parameters in 3 conditions: with nesting material with or without a shelter, comparing these 2 conditions to a "barren" regime without any enrichments. We studied a total of 360 mice from each of 2 mouse strains (C57BL/6NTac and DBA/2NCrl) and both sexes for each of the 3 conditions. Our study indicates that enrichment affects the mean values of some of the 164 parameters with no consistent effects on variability. However, the influence of enrichment appears negligible compared to the effects of other influencing factors. Therefore, nesting material and shelters may be used to improve animal welfare without impairment of experimental outcome or loss of comparability to previous data collected under barren housing conditions.
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Bienestar del Animal/ética , Ambiente Controlado , Comportamiento de Nidificación/fisiología , Bienestar del Animal/economía , Animales , Metabolismo Energético/fisiología , Femenino , Pruebas de Función Cardíaca/métodos , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Nocicepción/fisiologíaRESUMEN
By N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated the mutant mouse line TUB6 that is characterised by severe combined immunodeficiency (SCID) and systemic sterile autoinflammation in homozygotes, and a selective T cell defect in heterozygotes. The causative missense point mutation results in the single amino acid exchange G170W in multicatalytic endopeptidase complex subunit-1 (MECL-1), the ß2i-subunit of the immuno- and thymoproteasome. Yeast mutagenesis and crystallographic data suggest that the severe TUB6-phenotype compared to the MECL-1 knockout mouse is caused by structural changes in the C-terminal appendage of ß2i that prevent the biogenesis of immuno- and thymoproteasomes. Proteasomes are essential for cell survival, and defective proteasome assembly causes selective death of cells expressing the mutant MECL-1, leading to the severe immunological phenotype. In contrast to the immunosubunits ß1i (LMP2) and ß5i (LMP7), mutations in the gene encoding MECL-1 have not yet been assigned to human disorders. The TUB6 mutant mouse line exemplifies the involvement of MECL-1 in immunopathogenesis and provides the first mouse model for primary immuno- and thymoproteasome-associated immunodeficiency that may also be relevant in humans.
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Complejo de la Endopetidasa Proteasomal/inmunología , Animales , Supervivencia Celular/inmunología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Subunidades de Proteína/inmunologíaRESUMEN
Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored. Here, we report that old father offspring mice showed a reduced life span and an exacerbated development of aging traits compared with young father offspring mice. Genome-wide epigenetic analyses of sperm from aging males and old father offspring tissue identified differentially methylated promoters, enriched for genes involved in the regulation of evolutionarily conserved longevity pathways. Gene expression analyses, biochemical experiments, and functional studies revealed evidence for an overactive mTORC1 signaling pathway in old father offspring mice. Pharmacological mTOR inhibition during the course of normal aging ameliorated many of the aging traits that were exacerbated in old father offspring mice. These findings raise the possibility that inherited alterations in longevity pathways contribute to intergenerational effects of aging in old father offspring mice.
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Envejecimiento/genética , Epigénesis Genética , Longevidad , Factores de Edad , Envejecimiento/fisiología , Animales , Metilación de ADN , Padre , Femenino , Humanos , Esperanza de Vida , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Linaje , Regiones Promotoras Genéticas , Espermatozoides/metabolismoRESUMEN
The formation of amyloid fibrils by human islet amyloid polypeptide protein (hIAPP) has been implicated in pancreas dysfunction and diabetes. However, efficient treatment options to reduce amyloid fibrils in vivo are still lacking. Therefore, we tested the effect of epigallocatechin gallate (EGCG) on fibril formation in vitro and in vivo. To determine the binding of hIAPP and EGCG, in vitro interaction studies were performed. To inhibit amyloid plaque formation in vivo, homozygous (tg/tg), hemizygous (wt/tg), and control mice (wt/wt) were treated with EGCG. EGCG bound to hIAPP in vitro and induced formation of amorphous aggregates instead of amyloid fibrils. Amyloid fibrils were detected in the pancreatic islets of tg/tg mice, which was associated with disrupted islet structure and diabetes. Although pancreatic amyloid fibrils could be detected in wt/tg mice, these animals were non-diabetic. EGCG application decreased amyloid fibril intensity in wt/tg mice, however it was ineffective in tg/tg animals. Our data indicate that EGCG inhibits amyloid fibril formation in vitro and reduces fibril intensity in non-diabetic wt/tg mice. These results demonstrate a possible in vivo effectiveness of EGCG on amyloid formation and suggest an early therapeutical application.
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Amiloide/metabolismo , Amiloidosis/metabolismo , Catequina/análogos & derivados , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Fármacos Neuroprotectores/farmacología , Páncreas/metabolismo , Amiloide/química , Amiloidosis/patología , Animales , Biomarcadores , Catequina/química , Catequina/metabolismo , Catequina/farmacología , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Ratones , Ratones Transgénicos , Modelos Moleculares , Conformación Molecular , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/metabolismo , Páncreas/patología , Páncreas/ultraestructura , Unión ProteicaRESUMEN
Because of the increasing application of ionizing radiation in medicine, quantitative data on effects of low-dose radiation are needed to optimize radiation protection, particularly with respect to cataract development. Using mice as mammalian animal model, we applied a single dose of 0, 0.063, 0.125 and 0.5 Gy at 10 weeks of age, determined lens opacities for up to 2 years and compared it with overall survival, cytogenetic alterations and cancer development. The highest dose was significantly associated with increased body weight and reduced survival rate. Chromosomal aberrations in bone marrow cells showed a dose-dependent increase 12 months after irradiation. Pathological screening indicated a dose-dependent risk for several types of tumors. Scheimpflug imaging of the lens revealed a significant dose-dependent effect of 1% of lens opacity. Comparison of different biological end points demonstrated long-term effects of low-dose irradiation for several biological end points.