RESUMO
Variable number tandem repeat (VNTR) polymorphisms of the human neonatal IgG Fc receptor α-chain gene (FCGRT) are known to influence the expression levels of FCGRT and IgG in serum. Monkeys are considered to be a relevant biological model for studying the effects of immunobiological drugs. The study determined the functional VNTR polymorphisms of the FCGRT gene in 109 male rhesus macaques from the nursery of the Kurchatov Complex of Medical Primatology. PCR amplification of samples was carried out followed by electrophoretic separation of DNA fragments in a 2% agarose gel. Individual DNA amplification products were sequenced (according to Sanger system) in forward and reverse directions to confirm the specificity. The genotyping showed that the VNTR polymorphism of the FCGRT gene in the studied population of rhesus macaques is presented by 9 variants. The frequency of the VNTR5 allele associated with lower IgG levels was 14.2%, and the most common one was the VNTR7 allele (25.2%). We also identified alleles that have not been previously reported: VNTR3, VNTR4, VNTR6, VNTR8, and VNTR9. The study allows to consider rhesus macaques as a potential model for studying the immunological response depending on the genetic VNTR variant of FCGRT.
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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.
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Human rs6265 (196G>A) polymorphism in the BDNF gene is associated with many clinically significant phenotypic manifestations. Rhesus monkey (Macaca mulatta) has a functionally significant rs309950446 ( 136G>A) polymorphism. To determine this polymorphism in macaques, we used mismatch amplification mutation assay (MAMA)-PCR method with non-complementary nucleotide to the template chain at the 3rd position from the 3'-end of the allele-specific primers (mismatch primers), which allowed the best discrimination of the alleles. Genotyping of male rhesus monkeys (n=178) and cynomolgus monkeys (Macaca fascicularis) (n=90) was carried out. The A/A, G/G, and G/A genotypes were found in 16, 34, and 50% rhesus macaques, respectively. In the cynomolgus macaques, the mutant polymorphic allele was not detected. The study results allow considering rhesus macaques as a potential biological model for assessment of the gen-environment interaction of the BDNF gene polymorphism.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Polimorfismo Genético , Animais , Humanos , Masculino , Macaca mulatta/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Genótipo , Polimorfismo Genético/genética , Macaca fascicularis/genética , Reação em Cadeia da Polimerase , Mutação/genéticaRESUMO
In female Wistar rats, mammary gland hyperplasia (MGH) was modeled according to a modified protocol involving estrogen-progesterone induction and taking into account the duration of the estrous cycle of this animal species. MGH was induced over four 7-day cycles; each cycle included subcutaneous administration of 17ß-estradiol (0.5 mg/kg) for 4 days, injection of progesterone (5 mg/kg) on day 5, then 2 days without injections. In females with MGH, a significant increase in the height and diameter of the nipples of the mammary glands was recorded, two types of changes were observed in the gland tissue: tubuloalveolar and lobuloalveolar hyperplasia. The study confirmed the development of MGH in rats by a modified method.
Assuntos
Estrogênios , Progesterona , Ratos , Feminino , Animais , Progesterona/farmacologia , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Ratos Wistar , Estrogênios/farmacologia , Estradiol/farmacologia , Glândulas Mamárias Animais/patologiaRESUMO
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.
Assuntos
Neoplasias Pulmonares , Uretana , Feminino , Masculino , Camundongos , Animais , Uretana/efeitos adversos , Camundongos Endogâmicos BALB C , Carcinógenos , Carcinogênese , Amidas , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/prevenção & controle , Substâncias Protetoras , PulmãoRESUMO
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.
Assuntos
Dano ao DNA , Lignina , Animais , Ensaio Cometa , Metanossulfonato de Metila/toxicidade , Mutagênicos/toxicidade , Substâncias Protetoras , RatosRESUMO
Many natural substances exhibit anti-inflammatory activity and considerable potential in prophylaxis and treatment of allergies. Knowing exact molecular targets, which is required for developing these as medicinal products, is often challenging for multicomponent compositions. In the present study we examined novel polyphenolic substance, a water-soluble fraction of wood lignin (laboratory code BP-Cx-1). In our previous study, a number of polyphenolic components of BP-Cx-1 (flavonoids, sapogenins, phenanthrenes etc.) were identified as the major carriers of biological activity of BP-Cx drug family, and several molecular targets involved in cancer and/or inflammation signaling pathways were proposed based on the results of the in vitro and in silico screening studies. In the present study, half maximal inhibitory concentration (IC50) of BP-Cx-1 was established with a radioligand method and a range of IC50 values between 22.8 and 40.3 µg/ml were obtained for adenosine receptors A1, A2A and prostaglandin receptors EP2, IP (PGI2). IC50 for serotonin 5-HT1 and for glucocorticoid GR receptors were 3.0 µg/ml and 12.6 µg/ml, respectively, both being within the range of BP-Cx-1 concentrations achievable in in vivo models. Further, distribution of [3H] labelled BP-Cx-1 in NIH3T3 murine fibroblasts and MCF7/R carcinoma cells was studied with autoradiography. [3H]-BP-Cx-1 (visualized as silver grains produced by tritium beta particles) was mainly localized along the cell membrane, in the perinuclear region and in the nucleus, suggesting ability of BP-Cx-1 to enter cells and bind to membrane or cytosol receptors. In our experiment, we observed the effect of BP-Cx-1 on maturation of dendritic cells (DCs): downregulation of expression of the lipid-presentation molecule CD1a, co-stimulatory molecules CD80, CD83 and CD 40, decreased production of pro-inflammatory cytokines IL-4 and TNF-α and increased production of anti-inflammatory cytokine IL-10. It is hypothesized that [3H]-BP-Cx-1 detectable in the nucleus is part of the activated GR complex, known to be involved in regulation of transcription of genes responsible for the anti-inflammatory response. Based on IC50, cell distribution data and results of the experiment with DCs it is suggested that the in vivo effects of BP-Cx-1 are mediated via GR and 5-HT1 receptors thus promoting development of tolerogenic effector function in dendritic cells.
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Células Dendríticas , Lignina , Animais , Citocinas , Camundongos , Células NIH 3T3 , ÁguaRESUMO
To analyze experimental data on the effect of various polyphenolic compounds on lifespan of mice, we approximated survival curves with the Gompertz model in its minimal form, which does not account for the heterogeneity of samples and the age-independent mortality. The plots of regressions of logï0 (logarithm of the initial mortality) on ï§ (the rate of aging) in series of control samples were used to assess the deviations of vectors directed from control to experimental data from the slopes of the control regressions. The analysis of published data suggests that resveratrol, polyphenol-containing grape skin extract, metformin, tocopherol, and the antioxidant SkQ1 do not produce changes beyond those possible upon comparing of different samples of a control population. The effect of the polyphenolic composition BP-C3 on female SHR mice is unique in being associated with a significant decrease in the rate of aging. The effect may be partly contributed to by the antioxidant properties of BP-C3. Its antioxidant capacity determined in vitro is comparable with that of established antioxidants, such as dihydroquercetin. Its effects in vivo include the ability to ameliorate reduction in the peroxide-decomposing activity of RBC lysates from male BALB/c mice treated with 5-fluorouracil.
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Longevidade , Polifenóis , Animais , Antioxidantes/farmacologia , Feminino , Longevidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Polifenóis/farmacologia , Análise de SobrevidaRESUMO
Almost all the functions of a living organism have circadian oscillations. Disturbance of circadian rhythms can be either a reason or a consequence of a number of diseases. The article describes data on relationship of circadian rhythm and clock genes disturbances with type 2 diabetes mellitus, cardiovascular and neurodegenerative disease development in humans and animals.
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Envelhecimento/fisiologia , Doenças Cardiovasculares , Transtornos Cronobiológicos , Ritmo Circadiano/fisiologia , Diabetes Mellitus Tipo 2 , Doenças Neurodegenerativas , Proteínas Circadianas Period/análise , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Transtornos Cronobiológicos/metabolismo , Transtornos Cronobiológicos/fisiopatologia , Relógios Circadianos/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Fatores de RiscoRESUMO
Almost all the body's functions exhibit circadian rhythm maintained in a cell by a system of Clock genes and proteins. Failure to synchronize or loss of these rhythms are found in aged organism and are associated with risk of cancer development. The article describes data on mechanisms of circadian rhythms regulation in whole organism and cell, rhythm change during aging and relationship between rhythm disturbances and tumorigenesis of different localisations in humans and animals.
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Ritmo Circadiano , Neoplasias , Envelhecimento , Animais , HumanosRESUMO
Circadian rhythm disturbance promotes of carcinogenesis and is associated with changes in clock genes and proteins expression. In the current study we observed that continu- ous light exposure potentiated skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene and 12-0-tetradecanoylphor- bol-13-acetate while melatonin had opposite effect. Carcinogenic exposure decreased BMAL1 and CRYI- expression in the skin, CLOCK expression was upregulated and CRYl downregulated in tumor compared to normal skin. BMAL1 expression increased under disrupted light regimen; melatonin treatment affected CLOCK expression in tumors and CRYI in skin at the carcinogens application sites.
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Proteínas CLOCK/biossíntese , Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica , Iluminação , Proteínas de Neoplasias/biossíntese , Neoplasias Cutâneas/metabolismo , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Fatores de Transcrição ARNTL/biossíntese , Animais , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/patologia , Criptocromos/biossíntese , Masculino , Camundongos , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia , Acetato de Tetradecanoilforbol/toxicidadeRESUMO
Blood levels of vascular endothelial growth factor, the main marker of angiogenesis activity, and coagulation hemostasis were studied in CDF1 mice with transplanted P-388 lymphocytic leukemia. Blood levels of vascular endothelial growth factor increased by 168% in mice with tumors. The animals developed the hypercoagulation syndrome manifesting in shorter activated partial thromboplastin time and prothrombin time and development of hyperfibrinogenemia.
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Transtornos da Coagulação Sanguínea/fisiopatologia , Leucemia P388/fisiopatologia , Neovascularização Patológica/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/sangue , Animais , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Transplante de Neoplasias/fisiologia , Neovascularização Patológica/sangue , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Estatísticas não ParamétricasRESUMO
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.
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Adenocarcinoma/sangue , Envelhecimento/sangue , Biomarcadores Tumorais/sangue , Neoplasias Mamárias Animais/sangue , Neovascularização Patológica/sangue , Receptor ErbB-2/sangue , Adenocarcinoma/irrigação sanguínea , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Feminino , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Mamárias Animais/irrigação sanguínea , Neoplasias Mamárias Experimentais , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Óxido Nítrico/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativador de Plasminogênio Tecidual/sangue , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
There were obtained sufficient experimental evidence of the stimulating effect on the development of tumors (transplanted, spontaneous and induced by various carcinogenic agents), disorders of circadian function of the pineal gland (light-induced desynchronosis) caused by knockout or mutation of clock genes, pinealectomy, content in conditions of constant light or natural light regime of the North, as well as jetlag modeling in laboratory rodents. In experiments on various models of carcinogenesis it was found that sympathectomy (removal of the superior cervical ganglion), light deprivation, hibernation and application of melatonin, the natural hormone of the pineal gland, had an inhibitory effect on the development of transplanted, spontaneous and induced tumors of different histogenesis.
Assuntos
Relógios Biológicos , Ritmo Circadiano , Luz/efeitos adversos , Melatonina/metabolismo , Neoplasias Experimentais/prevenção & controle , Neoplasias Experimentais/fisiopatologia , Glândula Pineal/metabolismo , Animais , Animais de Laboratório , Antioxidantes/administração & dosagem , Relógios Biológicos/genética , Carcinógenos , Depressores do Sistema Nervoso Central/administração & dosagem , Ritmo Circadiano/genética , Técnicas de Inativação de Genes , Hibernação , Síndrome do Jet Lag , Melatonina/administração & dosagem , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/metabolismo , Glândula Pineal/cirurgia , Gânglio Cervical Superior/cirurgia , SimpatectomiaRESUMO
Influence of selenium on induced carcinogenesis of the prostate and other organs was studied in male Wistar rats. Carcinogenesis was induced (68) by using our modification of a combined double-stage model including surgical castration, single administration of N-methyl-N-nitrosourea (MNU) and long-term promotion by a mix of testosterone ethers (MTE). Seven days after MNU injection the rats were randomized to form 2 groups. Controls were fed drinking water while the study group - water containing sodium selenite 4mg/l, daily - till the end of the experiment. Controls (12) were not exposed to any treatment. They were followed up for 55 weeks until sacrificed. Apparent benign prostatic hyperplasia developed in rats subjected to castration, MNU and MTE. Also, such precancerous lesions as prostatic intraepithelial neoplasia (PIN) and prostate cancer including metastatic one were detected. Malignant lymphoma, other than in target tissues, was the most frequent. Prostate pathological changes and lymphomas were not registered in intact rats. Unlike rats treated with MNU and MTE and fed untreated drinking water, selenium did not influence significantly the development of prostate intraepithelial neoplasia but reduced multiplicity of prostate cancer by 44.6%. Simultaneously, the incidence of induced malignant lymphomas decreased by 26.4%.
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Anticarcinógenos/farmacologia , Linfoma/prevenção & controle , Lesões Pré-Cancerosas/prevenção & controle , Hiperplasia Prostática/prevenção & controle , Neoplasia Prostática Intraepitelial/prevenção & controle , Neoplasias da Próstata/prevenção & controle , Selenito de Sódio/farmacologia , Animais , Anticarcinógenos/administração & dosagem , Carcinógenos , Transformação Celular Neoplásica/efeitos dos fármacos , Água Potável , Linfoma/etiologia , Masculino , Metilnitrosoureia , Orquiectomia , Lesões Pré-Cancerosas/etiologia , Hiperplasia Prostática/etiologia , Neoplasia Prostática Intraepitelial/etiologia , Neoplasias da Próstata/etiologia , Ratos , Ratos Wistar , Selenito de Sódio/administração & dosagem , TestosteronaRESUMO
Antitumor activity of a new cytostatic drug combination of gemcitabine and dioxadet have been studied in 86 female SHR mice transplanted with 5 x 10(6) of ascitic Ehrlich's tumor cells each. All mice received a single injection of gemcitabine, dioxadet on combination 48 hams after tumor cells introduction. In first series, experimental animals received maximal tolerable dose of gemcitabine (25 mg/kg) and one half of dioxadet maximal tolerable dose (2.5 mg/kg). In the second series of experiments, the animals received 5 mg/kg of dioxadet along with the same gemcitabine dose. Effect of drugs was compared using the time to ascites detection, body weight increase, and survival time. Gemcitabine and dioxadet administered separately and in combination inhibited the growth of ascitic Ehrlich's tumor in the mice. In both series of experiments antineoplastic activity of gemcitabine and dioxadet combination was significantly higher in comparison to the control groups receiving these drugs separately. The highest antineoplastic activity of the gemcitabine and dioxadet combination was observed when the maximal tolerable doses of both drugs was applied. However, the tumor cells growth was also significantly inhibited in mice receiving half of dioxadet dose. Synergism of antitumor activity of gemcitabine and dioxadet was not accompanied by appreciable increase in toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Desoxicitidina/análogos & derivados , Triazinas/farmacologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Esquema de Medicação , Sinergismo Farmacológico , Feminino , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos , Fatores de Tempo , Triazinas/administração & dosagem , Aumento de Peso , GencitabinaRESUMO
Antitumor activity of dioxadet in comparison with cisplatin was studied on the model of ascitic ovarian tumor in 32 female Wistar rats. Ascitic ovarian tumor was transplanted intraperitoneally 0.5 ml per rat dissolved by saline in ratio 1 to 4. Dioxadet (1.5 mg/kg b.w.) and cisplatin (4.0 mg/kg b.w.) were administered intraperitoneally at their single maximal tolerable doses 48 hours after tumor cells transplantation. For drug activity estimation time to ascites detection and survival time values were used. In control group without no treatment the time till ascites occurrence and median life span were 5.4 +/- 0.25 and 7.5 days, correspondingly. In comparison with the control group dioxadet increased the average time of ascites occurrence and median of life span by 30% and 113% (p < 0.05), cisplatin increased these parameters by 28% and 147% (p < 0.05). Hence, antitumor activity of dioxadet is comparable with cisplatin activity for intraperitoneal therapy of the ascitic ovarian tumor.
Assuntos
Antineoplásicos/farmacologia , Ascite/etiologia , Cisplatino/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Triazinas/farmacologia , Animais , Feminino , Neoplasias Ovarianas/complicações , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
An electromagnetic wave (EMW) interacting with the moving singularity of the charged particle flux undergoes the reflection and absorption as well as frequency change due to Doppler effect and nonlinearity. The singularity corresponding to a caustic in plasma flow with inhomogeneous velocity can arise during the breaking of the finite amplitude Langmuir waves due to nonlinear effects. A systematic analysis of the wave-breaking regimes and caustics formation is presented and the EMW reflection coefficients are calculated.
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The effect of lighting and melatonin treatment on 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis was investigated in rats. There was a direct correlation between constant lighting, on the one hand, and the rate of the process, on the other, and an inverse one between light deprivation and melatonin treatment. That presented as changes in rate of tumorigenesis, number of tumors per animal, adenocarcinoma cell differentiation grade, invasiveness and proliferative rate. Our results point to light duration as a significant factor of colorectal cancer progression.