RESUMEN
A model for accelerated aging in mice was developed: CB6F2 mice aged 39-45 days were exposed to fractionated 4-fold relatively uniform γ-radiation (137Cs, 0.98 Gy/min) at a total dose of 6.8 Gy. Radiation exposure led to delayed active growth, leukopenia, and lymphopenia for over 1 year during the post-radiation period. The death of irradiated males and females occurred significantly earlier than in control group animals. Median lifespans in the experimental group were 35-38% lower than in the control group (p<0.001). Ionizing radiation exposure led to the early development of hair depigmentation, cachexia, and the development of aging-associated diseases. In irradiated mice, oncological pathology constituted 30-35% in the mortality structure, which is twice as often as in the control group. The developed model can be used to study the pathogenesis of accelerated aging under radiation exposure and the search for means of its prevention and treatment.
Asunto(s)
Envejecimiento Prematuro , Rayos gamma , Animales , Ratones , Masculino , Femenino , Rayos gamma/efectos adversos , Envejecimiento Prematuro/patología , Envejecimiento Prematuro/genética , Envejecimiento Prematuro/etiología , Longevidad/efectos de la radiación , Radiación Ionizante , Envejecimiento/efectos de la radiación , Caquexia/patología , Caquexia/etiología , Radioisótopos de CesioRESUMEN
Female C57BL/J mice with pulmonary fibrosis induced by injections of bleomycin (20 mg/kg intraperitoneally, 8 times for 4 weeks) were treated with a lignin derivative-based composition BP-C3 (80 mg/kg, daily intragastric administrations for 4 weeks). Bleomycin treatment increased the severity of pulmonary fibrosis (Ashcroft score increased from 1.43±0.20 to 4.17±0.48) and the percentage of α-SMA+ tissue (from 15.22±1.01 to 33.12±2.30%) and DNA-synthetizing nuclei (from 1.05±0.14 to 3.38±0.375). After treatment with BP-C3, we observed a tendency to a decrease in Ashcroft score (to 3.40±0.51) and a significant decrease in the percentage of α-SMA+ tissue to 24.30±1.70%; the percentage of DNA-synthetizing nuclei decreased to a lesser extent (to 3.03±0.22%). These results suggest that BP-C3 has a moderate antifibrotic activity.
Asunto(s)
Bleomicina , Lignina , Ratones Endogámicos C57BL , Fibrosis Pulmonar , Animales , Bleomicina/toxicidad , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Ratones , Femenino , Lignina/farmacología , Lignina/química , Pulmón/efectos de los fármacos , Pulmón/patología , Actinas/metabolismo , Actinas/genéticaRESUMEN
We studied the state of the DNA repair system and apoptosis in young mice carrying heterozygous inactivating mutation in the NBS1 gene (c.1971insT, p.Arg658Stop). In the peripheral blood cells of 4-month-old NBS1insT males, the %DNA in the comet tail was higher by 10% than in wild-type mice (wt) (p<0.05). In hepatocytes of NBS1insT mice, the proportion of γH2AX+ nuclear regions marking DNA double-strand breaks was lower by 2 times than in wt mice (p<0.05), which can be an indicator of less efficient DNA repair. In the kidney tissue of NBS1insT mice, a tendency towards the proapoptotic ratio of Bax and Bcl-2 protein markers was revealed against the background of their reduced expression. Thus, the disturbances detected NBS1insT mice in young age suggest that this model is promising for further studies of carcinogenesis.
Asunto(s)
Proteínas de Unión al ADN , Proteínas Nucleares , Masculino , Ratones , Animales , Proteínas de Unión al ADN/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Daño del ADN/genética , Reparación del ADN/genética , ADN , Mutación , Apoptosis/genéticaRESUMEN
We studied the effects of polyphenolic composition BP-C2, comprising molybdenum with lignin derivatives, on lung carcinogenesis induced by urethane in the progeny of F0 male BALB/c mice preconceptionally exposed to radiation in a dose of 1 Gy. The multiplicity of lung tumors in the progeny of irradiated mice was higher than in the progeny of non-irradiated male parents by 50% in females and 43% in males (p<0.05). In F1 mice (progeny of irradiated F0 male parents treated with BP-C2), the multiplicity of lung tumors was also higher, but this increase was less pronounced: 35% in females (p=0.3852) and 23% in males (p=0.0766). We have demonstrated that administration of BP-C2 to irradiated parents (F0) efficiently inhibits carcinogenesis in their F1 progeny. The use of BP-C2 in irradiated male parents and their progeny not only reduced the multiplicity of tumors, but also normalized body weights in the F1 progeny. Our study demonstrates potential of the polyphenolic composition BP-C2 for chemoprophylaxis of radiation-induced transgenerational carcinogenesis.
Asunto(s)
Neoplasias Pulmonares , Uretano , Femenino , Masculino , Ratones , Animales , Uretano/efectos adversos , Ratones Endogámicos BALB C , Carcinógenos , Carcinogénesis , Amidas , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/prevención & control , Sustancias Protectoras , PulmónRESUMEN
The genotoxic and antigenotoxic potential of BP-C2, a novel lignin-derived polyphenolic composition with ammonium molybdate, was investigated as a radioprotector/radiomitigator for civil applications and as a medical countermeasure for radiation emergencies. Using the alkaline comet assay and methyl methanesulfonate (MMS, 40 mg/kg) as the DNA-damaging agent, these effects of BP-C2 on liver, bone marrow cells and blood leukocytes in rats were studied. The DNA damage was estimated by the DNA content in the comet tail (TDNA, %) 1, 6 and 18 h post exposure to MMS. BP-C2 at doses of 20, 200 and 2000 mg/kg did not exert genotoxic activity in the tested tissues in rats. BP-C2 administered at doses of 20, 100 and 200 mg/kg 1 h before MMS significantly (p < 0.01) mitigated MMS-induced DNA damage, showing a strong genoprotective effect in the liver. In blood leukocytes and bone marrow samples of animals treated with BP-C2, the TDNA % was slightly higher than in the negative control (vehicle) but significantly lower than in the positive control (MMS). Thus, BP-C2 exerted a genoprotective effect against MMS-induced DNA damage to a greater extent towards liver cells, requiring further evaluation of this substance as a genoprotective agent.
Asunto(s)
Daño del ADN , Lignina , Animales , Ensayo Cometa , Metilmetanosulfonato/toxicidad , Mutágenos/toxicidad , Sustancias Protectoras , RatasRESUMEN
Melatonin was administered at the dose of 1,2 mcg per capita (an equivalent to pediatric dosages) at days 1, 3 and 5 postpartum to 129/Sv mice, which were followed thereafter till their natural deaths. In adult males, findings included a decrease in body weight and an increase in the contribution of pulmonary lesions, which were revealed upon postmortem examinations, to the overall mortality. In adult females, no changes in body weight occurred, the proportion of middle- and late-age mice having irregular estrous cycles increased, and mortality associated with uterine hemangiomas was accelerated. Trends in malignant tumor yields were different: a decrease in males and an increase in females. Tends in survival patterns were expressed as significant increases or decreases in the lifespans of the last 25% and 10% of male or female survivors respectively. An analysis of the complete survivorships curves in terms of the Gompertz model showed that changes in the initial mortality and aging rate were within the limits determined by the artifactual component of the Strehler-Mildvan correlation between these parameters. On a whole, the trends found in the present work were opposite in males and females being mostly favorable for the former and adverse for the latter. Gender specificity should be kept in mind upon considering the use of melatonin by children and their mothers.
Asunto(s)
Antioxidantes , Longevidad , Melatonina , Animales , Antioxidantes/farmacología , Peso Corporal , Niño , Femenino , Humanos , Recién Nacido , Masculino , Melatonina/farmacología , Ratones , Ratones Endogámicos , Factores SexualesRESUMEN
The review describes the experimental and clinical data of the last decades on the use of geroprotective preparations of mTOR inhibitors group for the main and accompanying treatment of cancer patients. mTOR protein kinase is an perspective therapeutic target for the treatment of multiple cancers, both with the mTOR inhibitors themselves (rapamycin and its derivatives) and in combination with inhibitors of other pathways (for example, metformin). The mTOR inhibitors, not being classical cytostatics and not having carcinogenic activity, have great prospects for use both as independent antitumor agents and for use in combination with conventional chemotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Metformina/uso terapéutico , Sirolimus/uso terapéuticoRESUMEN
The critical analysis of preclinical testing of anticarcinogenic and antitumor activity of biguanides presented in this paper. Experiments have been conducted using in total more than 20 models of carcinogenesis including models of spontaneous , chemically- , radiation- and virus-induced carcinogenesis, as well as carcinoigenesis induced by special fat diets and by genetic modification in rodents. Cancer preventive effect of buiguanides has been studied in relation to total tumor incidence and to 17 target organs in animals of 3 species, including 25 various strains of mice, 4 strains of rats and 1 strain of hamsters using various routs of administration and doses. In the majority of cases (86%) the exposure to biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed, however there was no any case of stimulation of carcinogenesis by antidiabetic biguanides., Metformin suppressed tumor growth in the majority of in vitro studies conducted in 46 different cell lines originated from malignant tumors of 15 localization as well as in athymic mice with xenografts of 31 tumor lines. It was concluded that there are sufficient experimental evidences of anticarcinogenic and antitumor effects of antidiabetic biguanides revealed in a number of models of induced and spontaneous carcinogenesis.
Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Neoplasias Experimentales/prevención & control , Animales , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Humanos , Ratones , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , RatasRESUMEN
Age-dependent angiogenesis intensity changes have been studied in transgenic HER-2/neu (FBV/N) mice characteristic of breast tumors' high incidence with hyperexpression of HER-2/neu. Concentration of vascular endothelial growth factor, insulin-dependent growth factor 1, nitrogen monoxide, tissue plasminogen activator and type 1 plasminogen activator inhibitor were assessed by means of immune-enzyme assay. The results testify to angiogenesis processes activation side by side with aging and growth of the tumors. Maximum manifestation of these disturbances (growth factors' blood concentrations increase and endotheliocytes' functional activity inhibition) has been revealed in 6-month-old mice during neoplasma maximum intensive and aggressive growth period.
Asunto(s)
Adenocarcinoma/sangre , Envejecimiento/sangre , Biomarcadores de Tumor/sangre , Neoplasias Mamarias Animales/sangre , Neovascularización Patológica/sangre , Receptor ErbB-2/sangre , Adenocarcinoma/irrigación sanguínea , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Femenino , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Mamarias Animales/irrigación sanguínea , Neoplasias Mamarias Experimentales , Ratones , Ratones Endogámicos , Ratones Transgénicos , Óxido Nítrico/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Activador de Tejido Plasminógeno/sangre , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Very low (nano- and subnanomolar) concentrations of 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) were found to prolong lifespan of a fungus (Podospora anserina), a crustacean (Ceriodaphnia affinis), an insect (Drosophila melanogaster), and a mammal (mouse). In the latter case, median lifespan is doubled if animals live in a non-sterile vivarium. The lifespan increase is accompanied by rectangularization of the survival curves (an increase in survival is much larger at early than at late ages) and disappearance of typical traits of senescence or retardation of their development. Data summarized here and in the preceding papers of this series suggest that mitochondria-targeted antioxidant SkQ1 is competent in slowing down execution of an aging program responsible for development of age-related senescence.