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1.
Cancer Sci ; 111(3): 840-848, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925975

RESUMO

Ionizing radiation can damage DNA and, therefore, is a risk factor for cancer. Eker rats, which carry a heterozygous germline mutation in the tumor-suppressor gene tuberous sclerosis complex 2 (Tsc2), are susceptible to radiation-induced renal carcinogenesis. However, the molecular mechanisms involved in Tsc2 inactivation are unclear. We subjected Fischer 344 × Eker (Long Evans Tsc2+/- ) F1 hybrid rats to gamma-irradiation (2 Gy) at gestational day 19 (GD19) or postnatal day 5 (PND5) and investigated the patterns of genomic alterations in the Tsc2 allele of renal tumors that developed at 1 year after irradiation (N = 24 tumors for GD19, N = 10 for PND5), in comparison with spontaneously developed tumors (N = 8 tumors). Gamma-irradiation significantly increased the multiplicity of renal tumors. The frequency of LOH at the chromosome 10q12 region, including the Tsc2 locus, was 38%, 29% and 60% in renal carcinomas developed from the nonirradiated, GD19 and PND5 groups, respectively. Array comparative genomic hybridization analysis revealed that the LOH patterns on chromosome 10 in renal carcinomas were classified into chromosomal missegregation, mitotic recombination and chromosomal deletion types. LOH of the interstitial chromosomal deletion type was observed only in radiation-associated carcinomas. Sequence analysis for the wild-type Tsc2 allele in the LOH-negative carcinomas identified deletions (nonirradiated: 26%; GD19: 21%) and base-substitution mutations (GD19: 4%). Reduced expression of Tsc2 was also observed in the majority of the LOH-negative carcinomas. Our results suggest that interstitial chromosomal deletion is a characteristic mutagenic event caused by ionizing radiation, and it may contribute to the assessment of radiation-induced cancer risk.


Assuntos
Neoplasias Renais/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/genética , Alelos , Animais , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Hibridização Genômica Comparativa/métodos , Raios gama/efeitos adversos , Heterozigoto , Humanos , Masculino , Mutação/genética , Ratos , Ratos Endogâmicos F344 , Ratos Long-Evans , Risco , Proteínas Supressoras de Tumor/genética
2.
Int J Radiat Biol ; 96(1): 100-111, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-29447591

RESUMO

Purpose: Characterization of a novel partial-body irradiation (PBI) shielding strategy in nonhuman primates (NHP; rhesus macaques), aimed at protecting the oral cavity, with respect to various gastrointestinal acute radiation syndrome (GI-ARS) syndrome parameters as well as buccal ulceration development.Materials and methods: NHPs were irradiated using a Cobalt-60 gamma source, in a single uniform dose, ranging from 9-13 Gy and delivered at 0.60-0.80 Gy min-1. Animals were either partially shielded via oral cavity shielding (PBIOS) or underwent total-body irradiation (TBI).Results: Clinical manifestations of GI-ARS, and also radiation-induced hematology and clinical chemistry changes, following PBIOS were comparable to the PBI NHP GI-ARS model utilizing shielding of the distal pelvic limbs and were significantly milder than TBI at similar radiation doses. Nadir citrulline levels were comparable between PBIOS and TBI but signs of recovery appeared earlier in PBIOS-treated animals. The PBIOS model prevented oral mucositis, whereas the TBI model presented buccal ulcerations at all tested radiation dose levels.Conclusions: Taken together, these results suggest that the PBIOS model is a suitable alternative to traditional PBI. For GI-ARS investigations requiring orally administered medical countermeasures, PBIOS confers added value due to the prevention of oral mucositis over traditional PBI.


Assuntos
Boca/efeitos da radiação , Proteção Radiológica/métodos , Síndrome Aguda da Radiação/sangue , Síndrome Aguda da Radiação/etiologia , Síndrome Aguda da Radiação/patologia , Animais , Citrulina/sangue , Radioisótopos de Cobalto/efeitos adversos , Raios gama/efeitos adversos , Macaca mulatta , Masculino , Análise de Sobrevida , Úlcera/sangue , Úlcera/etiologia , Úlcera/patologia
3.
Pak J Pharm Sci ; 32(4): 1589-1597, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608878

RESUMO

The current study was designed to estimate the effect of υ-radiation on male rats pretreated with Levetiracetam (LEV) and/or Oxcarbazepine (OXC). Poly-treatment of rats with LEV, OXC and υ-radiation showed a significant elevation in the activity of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and isoenzyme creatinine kinase-MB (CK-MB) along with, an increase in the level of creatinine, urea, cardiac troponin (cTnI) and glutamate. These increases were associated with a decrease in acetylcholine (Ach) and υ-aminobutyric acid (GABA) levels. The data further revealed a significant increase of the apoptotic mediators tumor necrosis factor alpha (TNF-α) and brain caspase3 as well as, alterations in the oxidative stress parameters. The Results of the histopathological examination of liver, kidney, heart and brain tissues indicated coincidence with those recorded by the biochemical analysis. It seems promising to conclude that the exposure to υ-radiation intensified the deleterious and detrimental effect of dual treatment of LEV and OXC in rats.


Assuntos
Anticonvulsivantes/farmacologia , Raios gama/efeitos adversos , Levetiracetam/efeitos adversos , Oxcarbazepina/efeitos adversos , Acetilcolina/metabolismo , Alanina Transaminase/sangue , Animais , Anticonvulsivantes/efeitos adversos , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/efeitos da radiação , Quimioterapia Combinada , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/efeitos da radiação , Levetiracetam/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/efeitos da radiação , Masculino , Malondialdeído/metabolismo , Neurotransmissores/metabolismo , Oxcarbazepina/farmacologia , Ratos
4.
Oxid Med Cell Longev ; 2019: 3173745, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531182

RESUMO

Premature ovarian failure (POF) is a common cause of infertility in premenopausal women who are unavoidably exposed to cytotoxic therapy. Radiotherapy is one of the most effective cytotoxic treatments. However, the radiosensitivity of ovarian tissues limits its therapeutic outcome and results in the depletion of the primordial follicle and loss of fertility. Therefore, the need for an effective radioprotective therapy is evident especially when none of the current clinically used modalities for radioprotection succeeds efficiently. The present study investigated the potential radioprotective effect of carvacrol (CAR) (80 mg) or thymol (80 mg) on gamma- (γ-) irradiation-induced ovarian damage as well as their role in the cross-talk between IGF-1 and TNF-α signaling and antioxidative activity. In immature female Wister rats, a single dose of whole-body irradiation (3.2 Gy, LD20) produced considerable ovarian damage, which was evident by histopathological findings and hormonal changes. Interestingly, pretreatment with CAR or thymol significantly enhanced the follicular development and restored the anti-Mullerian hormone (AMH), E2, and FSH levels. Both essential oils improved the irradiation-mediated oxidative stress and reduction in proliferating cell nuclear antigen (PCNA) expression. Moreover, irradiated rats exhibited an inverse relationship between IGF-1 and TNF-α levels two days post irradiation, which was further inverted by the pretreatment with CAR and thymol and ought to contribute in their radioprotective mechanisms. In conclusion, CAR and thymol showed a radioprotective effect and rescued the ovarian reserve mainly through counteracting oxidative stress and the dysregulated cross-talk between IGF-1 and TNF-α.


Assuntos
/farmacologia , Raios gama/efeitos adversos , Fator de Crescimento Insulin-Like I/metabolismo , Insuficiência Ovariana Primária/sangue , Protetores contra Radiação/farmacologia , Transdução de Sinais , Timol/farmacologia , Fator de Necrose Tumoral alfa/sangue , Animais , Feminino , Insuficiência Ovariana Primária/etiologia , Radioterapia/efeitos adversos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
5.
Mol Immunol ; 114: 578-590, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31526941

RESUMO

Immune system is a critical modulator of radiation-induced biological effects. In this study, we have assessed protective potential of N-acetyl tryptophan glucoside (NATG) pre-treatment in bone marrow of gamma radiation challenged mice. Isolated bone marrow cells were analysed for cell cycle progression by flow cytometry, while various pro-/anti-inflammatory cytokine profiles were performed by ELISA method. Overall radioprotective ability of NATG in ensuring protection against gamma radiation-induced damage was assessed by evaluating whole body survival analysis and haematological studies on 9 Gy irradiated mice with/without NATG pre-treatment. Results exhibited pre-treatment with 150 mg/kg b.wt oral administration of NATG as most effective against 9 Gy radiation exposure. Moreover, NATG showed non-interfering effect on cell cycle progression in pre-treated irradiated mice group when compared to radiation alone group. In addition, cytokine expression analysis indicated significant (p > 0.05) elevation in levels of IFN-γ, IL-2, IL-12, IL-13 and IL-17 in NATG pre-treated irradiated mice in comparison to radiation alone group. On the contrary, NATG pre-treatment was observed to alleviate levels of TNF-α and IL-10 significantly (p < 0.05) in radiated group as compared to only irradiated mice group. Furthermore, NATG pre-treatment to 9 Gy radiation exposed mice aided in restoring their haematological parameters in terms of haemoglobin counts, RBC counts, WBC counts, hematocrit levels, platelets and granulocyte levels in comparison to irradiated alone mice, thus enhancing their immune system and contributing towards a better survival against gamma radiation-induced deleterious effects. Conclusively, this study highlights the potential of NATG as a prospective radiation countermeasure agent against ionizing radiation-induced assaults to the immune system.


Assuntos
Raios gama/efeitos adversos , Imunossupressão/efeitos adversos , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-17/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Triptofano/análogos & derivados , Triptofano/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
6.
Mol Immunol ; 114: 561-570, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31522074

RESUMO

Autism is a neurodevelopmental disorder characterized by deficits and qualitative impairments in communication and implicit skill learning. Its prevalence is higher than previous estimates, and treatments have limited efficacy and are costly. Here, we assessed the therapeutic potential of JNJ77777120 (JNJ), a histamine-4 receptor (H4R) antagonist, using BTBR T+ Itpr3tf/J (BTBR) mice, a confirmed model of autism, and C57BL/6J (C57) mice, a commonly chosen reference strain. We first examined the effects of JNJ treatment on BTBR mice exposed to gamma-rays (irradiation-exposed) using a three-chambered apparatus. We further investigated the possible molecular mechanisms through which JNJ administration modulates IL-17A-, RORγT-, IL-22-, T-bet-, STAT3-, ICOS-, and Foxp3-producing CD8+ T cells in the spleens of irradiation-exposed BTBR mice. The effects of JNJ administration on the mRNA and protein expression of IL-17A, RORγT, IL-22, T-bet, STAT-3, pSTAT3, IL-10, and Foxp3 in brain tissue were also explored. Results showed that JNJ treatment with irradiation exposure increased social interactions in BTBR mice compared to that in irradiation-exposed BTBR mice. Additionally, JNJ-treated and irradiation-exposed BTBR mice exhibited decreases in IL-17A-, RORγT-, IL-22-, T-bet-, and STAT3-producing CD8+ T cells and increases in ICOS- and Foxp3-producing CD8+ T cells. Moreover, JNJ treatment and irradiation exposure in BTBR mice regulated the mRNA and protein expression levels of IL-17A, RORγT, IL-22, T-bet, STAT3, pSTAT-3, IL-10, and Foxp3 in the brain tissue. These results suggest that JNJ is useful for the treatment of autism, as this H4R antagonist could block inflammatory cytokine production and transcription factor signaling.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Indóis/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Piperazinas/farmacologia , Receptores Histamínicos H4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteínas com Domínio T/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Raios gama/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas/metabolismo
7.
Int J Radiat Biol ; 95(12): 1613-1626, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31498026

RESUMO

Purpose: The aim of this paper was to investigate the sequence preference of ionizing radiation (IR)-induced DNA damage as assessed by a linear amplification/polymerase stop (LA/PS) assay. The LA/PS assay is able to detect a wide range of IR-induced DNA lesions and this technique was utilized to quantitatively determine the preferential sites of gamma irradiation-induced DNA lesions in three different DNA sequences.Materials and methods: This analysis was performed on an automated DNA sequencer with capillary electrophoresis and laser-induced fluorescence detection.Results: The main outcome of this study was that G nucleotides were preferentially found at IR-induced polymerase stop sites. The individual nucleotides at the IR-induced DNA damage sites were analyzed and a consensus sequence of 5'-GG* (where * indicates the damaged nucleotide) was observed. In a separate method of analysis, the dinucleotides and trinucleotides at the IR-induced DNA damage sites were examined and 5'-GG* and 5'-G*G dinucleotides and 5'-GG*G trinucleotides were found to be the most prevalent. The use of the LA/PS assay permits a large number of IR-induced DNA lesions to be detected in the one procedure including: double- and single-strand breaks, apurinic/apyrimidinic sites and base damage.Conclusions: It was concluded that 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-G) and the degradation products of 8-oxoG were possibly the main lesions detected. To our knowledge, this is the first occasion that the DNA sequence preference of IR-induced DNA damage as detected by a LA/PS assay has been reported.


Assuntos
Dano ao DNA , DNA Polimerase Dirigida por DNA/metabolismo , Raios gama/efeitos adversos , Sequência de Bases , Oligonucleotídeos/genética , Plasmídeos/genética
8.
Radiat Res ; 192(4): 451-455, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31390311

RESUMO

Calorie restriction is known to influence several physiological processes and to alleviate the late effects of radiation exposure such as neoplasm induction and life shortening. However, earlier related studies were limited to acute radiation exposure. Therefore, in this study we examined the influence of chronic low-dose-rate irradiation on lifespan. Young male B6C3F1/Jcl mice were divided randomly into two groups, which were fed either a low-calorie (65 kcal/ week) or high-calorie (95 kcal/week) diet. The latter is comparable to ad libitum feeding. The animals in the irradiated group were continuously exposed to gamma rays for 400 days at 20 mGy/day, resulting in a total dose of 8 Gy. Exposure and calorie restriction were initiated at 8 weeks of age and the diets were maintained for life. The life-shortening effects from chronic whole-body irradiation were compared between the groups. Body weights were reduced in calorie-restricted mice irrespective of radiation treatment. Radiation induced a shortened median lifespan in both groups, but to a greater extent in the calorie-restricted mice. These results suggest that calorie restriction may sensitize mice to chronic low-dose-rate radiation exposure to produce a life-shortening effect rather than alleviating the effects of radiation.


Assuntos
Restrição Calórica , Longevidade/efeitos da radiação , Doses de Radiação , Animais , Raios gama/efeitos adversos , Masculino , Camundongos , Modelos de Riscos Proporcionais , Fatores de Tempo
9.
Exp Mol Pathol ; 111: 104299, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31442446

RESUMO

Curcumin (CUR) and silymarin (SLM) are powerful antioxidant and anti-inflammatory compounds with beneficial protective effects against renal diseases. The purpose of this study was to evaluate the efficacy of CUR and SLM alone or in combination on radiation (IR) induced kidney injury. The results showed that CUR and SLM alone or in combination attenuated the oxidative stress denoted by a reduction in the level of malondialdehyde (MDA), hydrogen peroxide (H2O2) and advanced oxidation protein products (AOPP) along with a marked increase of glutathione GSH content and total antioxidant capacity (TAC). Additionally, a significant decrease in the level of blood urea nitrogen (BUN), creatinine, Cystatin-C (CYT-C), neutrophil gelatinase-associated lipocalin (N-GAL) and Kidney Injury Molecule-1 (Kim-1) was recorded. Moreover, the treatment resulted in a remarkable decline in the serum levels of interleukin-18(IL-18), tumor necrosis factor- alpha (TNF-α), C reactive protein (CRP), BCL2 associated X protein (Bax), Factor-related Apoptosis (FAS) and the activity of Caspase-3 associated by an increase of B-cell CLL/lymphoma 2 (Bcl2) level. The results were confirmed with the histopathological examination. Kidney of irradiated showed glomerular atrophy, massive necrotic changes of expanded tubules with hyaline cast inside some tubules and apoptotic changes were recorded in some renal tubules. While irradiated rats treated with CUR and SLM exhibited marked preservation of the cellular structure of their kidney tissue. In conclusion, the combination of CUR and SLM could be more potent than a single agent on the biochemical and histological changes of the irradiated rat renal tissue.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Curcumina/farmacologia , Raios gama/efeitos adversos , Nefropatias/tratamento farmacológico , Silimarina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Quimioterapia Combinada , Mediadores da Inflamação/metabolismo , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
10.
Oxid Med Cell Longev ; 2019: 1486232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467629

RESUMO

Ionizing radiation-induced cardiovascular diseases (CVDs) have been well documented. However, the mechanisms of CVD genesis are still not fully understood. In this study, human umbilical vein endothelial cells (HUVECs) were exposed to gamma irradiation at different doses ranging from 0.2 Gy to 5 Gy. Cell viability, migration ability, permeability, oxidative and nitrosative stresses, inflammation, and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway activation were evaluated postirradiation. It was found that gamma irradiation at doses ranging from 0.5 Gy to 5 Gy inhibited the migration ability of HUVECs without any significant effects on cell viability at 6 h and 24 h postirradiation. The decreased transendothelial electrical resistance (TEER), increased permeability, and disruption of cellular junctions were observed in HUVECs after gamma irradiation accompanied by the lower levels of junction-related proteins such as ZO-1, occludin, vascular endothelial- (VE-) cadherin, and connexin 40. The enhanced oxidative and nitrosative stresses, e.g., ROS and NO2 - levels and inflammatory cytokines IL-6 and TNF-α were demonstrated in HUVECs after gamma irradiation. Western blot results showed that protein levels of mitogen-activated protein kinase (MAPK) pathway molecules p38, p53, p21, and p27 increased after gamma irradiation, which further induced the activation of the NF-κB pathway. BAY 11-7085, an inhibitor of NF-κB activation, was demonstrated to partially block the effects of gamma radiation in HUVECs examined by TEER and FITC-dextran permeability assay. We therefore concluded that the gamma irradiation-induced disruption of cellular junctions in HUVECs was through the inflammatory MAPK/NF-κB signaling pathway.


Assuntos
Raios gama/efeitos adversos , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Humanos
11.
Adv Exp Med Biol ; 1155: 729-738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468443

RESUMO

Gamma ray irradiation causes immune suppression, in which oxidative stress reduces cell viability and damages immune cells. In the present study, we investigated whether Loliolus beka gray meat (LBM), which contains large amounts of taurine, protects against damage of murine splenocytes by oxidative stress. An aqueous extract of LBM (LBMW) was prepared, which contained plentiful levels of taurine. LBMW improved cell viability of gamma ray-irradiated murine splenocytes, an effect that was associated with significant reduction in the production of reactive oxygen species (ROS). We also showed that the production of nitric oxide (NO) and ROS in gamma ray-irradiated zebrafish embryos, as well as the death of the embryos, were diminished by LBMW. These data suggest that the consumption of taurine-rich foods, such as LBM, may be used in the protection of cells against oxidative stress.


Assuntos
Extratos Celulares/farmacologia , Decapodiformes/química , Estresse Oxidativo , Protetores contra Radiação/farmacologia , Taurina/farmacologia , Animais , Células Cultivadas , Raios gama/efeitos adversos , Carne , Camundongos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Baço/citologia
12.
Radiat Res ; 192(4): 440-450, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393823

RESUMO

Radiotherapy to treat brain tumors can potentially harm the central nervous system (CNS). The radiation stimulates a series of immune responses in both the CNS as well as peripheral immune system. To date, studies have mostly focused on the changes occurring in the immune response within the CNS. In this study, we investigated the effect of γ-ray-induced CNS injury on the peripheral immune response using a cell co-culture model and a whole-brain irradiation (WBI) rat model. Nerve cells (SH-SY5Y and U87 MG cells) were γ-ray irradiated, then culture media of the irradiated cells (conditioned media) was used to culture immune cells (THP-1 cells or Jurkat cells). Analyses were performed based on the response of immune cells in conditioned media. Sprague-Dawley rats received WBI at different doses, and were fed for one week to one month postirradiation. Spleen and peripheral blood were then isolated and analyzed. We observed that the number of monocytes in peripheral blood, and the level of NK cells and NKT cells in spleen increased after CNS injury. However, the level of T cells in spleen did not change and the level of B cells in the spleen decreased after γ-ray-induced CNS injury. These findings indicate that CNS injury caused by ionizing radiation induces a series of changes in the peripheral immune system.


Assuntos
Sistema Nervoso Central/lesões , Sistema Nervoso Central/efeitos da radiação , Raios gama/efeitos adversos , Lesões Experimentais por Radiação/imunologia , Animais , Diferenciação Celular/efeitos da radiação , Linhagem Celular Tumoral , Sistema Nervoso Central/patologia , Quimiocinas/sangue , Quimiotaxia/efeitos da radiação , Humanos , Imunidade Inata/efeitos da radiação , Masculino , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Sprague-Dawley , Irradiação Corporal Total/efeitos adversos
13.
Planta ; 250(5): 1567-1590, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31372744

RESUMO

MAIN CONCLUSION: Persistent DNA damage in gamma-exposed Norway spruce, Scots pine and Arabidopsis thaliana, but persistent adverse effects at the organismal and cellular level in the conifers only. Gamma radiation emitted from natural and anthropogenic sources may have strong negative impact on plants, especially at high dose rates. Although previous studies implied different sensitivity among species, information from comparative studies under standardized conditions is scarce. In this study, sensitivity to gamma radiation was compared in young seedlings of the conifers Scots pine and Norway spruce and the herbaceous Arabidopsis thaliana by exposure to 60Co gamma dose rates of 1-540 mGy h-1 for 144 h, as well as 360 h for A. thaliana. Consistent with slightly less prominent shoot apical meristem, in the conifers growth was significantly inhibited with increasing dose rate ≥ 40 mGy h-1. Post-irradiation, the conifers showed dose-rate-dependent inhibition of needle and root development consistent with increasingly disorganized apical meristems with increasing dose rate, visible damage and mortality after exposure to ≥ 40 mGy h-1. Regardless of gamma duration, A. thaliana showed no visible or histological damage or mortality, only delayed lateral root development after ≥ 100 mGy h-1 and slightly, but transiently delayed post-irradiation reproductive development after ≥ 400 mGy h-1. In all species dose-rate-dependent DNA damage occurred following ≥ 1-10 mGy h-1 and was still at a similar level at day 44 post-irradiation. In conclusion, the persistent DNA damage (possible genomic instability) following gamma exposure in all species may suggest that DNA repair is not necessarily mobilized more extensively in A. thaliana than in Norway spruce and Scots pine, and the far higher sensitivity at the organismal and cellular level in the conifers indicates lower tolerance to DNA damage than in A. thaliana.


Assuntos
Arabidopsis/efeitos da radiação , Raios gama/efeitos adversos , Picea/efeitos da radiação , Pinus sylvestris/efeitos da radiação , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Noruega , Picea/genética , Picea/crescimento & desenvolvimento , Pinus sylvestris/genética , Pinus sylvestris/crescimento & desenvolvimento , Plântula/genética , Plântula/efeitos da radiação
14.
Int J Mol Sci ; 20(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323921

RESUMO

Exposure to ionizing radiation induces a complex cascade of systemic and tissue-specific responses that lead to functional impairment over time in the surviving population. However, due to the lack of predictive biomarkers of tissue injury, current methods for the management of survivors of radiation exposure episodes involve monitoring of individuals over time for the development of adverse clinical symptoms and death. Herein, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that were exposed to a single dose of 7.2 Gy whole-body 60Co γ-radiation that either survived or succumbed to radiation toxicities over a 60-day period. This study involved the delineation of the radiation effects in the liver, kidney, jejunum, heart, lung, and spleen. We found robust metabolic changes in the kidney and liver and modest changes in other tissue types at the 60-day time point in a cohort of NHPs. Remarkably, we found significant elevation of long-chain acylcarnitines in animals that were exposed to radiation across multiple tissue types underscoring the role of this class of metabolites as a generic indicator of radiation-induced normal tissue injury. These studies underscore the utility of a metabolomics approach for delineating anticipatory biomarkers of exposure to ionizing radiation.


Assuntos
Raios gama/efeitos adversos , Radiação Ionizante , Animais , Biomarcadores/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Rim/efeitos dos fármacos , Rim/metabolismo , Macaca mulatta , Masculino , Metabolômica/métodos , Primatas
15.
Cryo Letters ; 40(4): 200-208, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31278400

RESUMO

BACKGROUND: Glycerol, sucrose and trehalose are used as protectants for membrane, protein, cell and tissue preservation. The undercooled state (glassy or rubbery) of their solutions may also offer protection for protein, cells and tissues against radiation damage upon sterilization. OBJECTIVE: The study aimed to examine the protective effects of glycerol, sucrose and trehalose on cryopreserved acellular human dermis against gamma irradiation damage. MATERIALS AND METHODS: Acellular human dermis was cryopreserved at -80°C in glycerol, sucrose and trehalose solutions or their combinations with a base citrate-phosphate buffer (pH 6.0). Cryopreserved acellular dermis was then subjected to 13 kGy gamma irradiation at -78.5°C, and radiation damage was assessed by histological evaluation. RESULTS: Freeze and thaw alone do not alter the structure of acellular dermis, but gamma irradiation at -78.5°C results in significant structural changes in acellular dermis, including the formation of large holes, the damage of collagen fibers and the loss of overall dermis tissue histology. The incorporation of glycerol, sucrose and trehalose into cryopreservation solutions reduces gamma irradiation-induced tissue structural damage considerably. When used alone, trehalose (0.5 M) provided better protection against gamma irradiation damage than did sucrose (0.5 M) and glycerol (1.0 M). When used in combination, the glycerol and trehalose combination provides the best tissue protection. Significant donor-to-donor variation exists in tissue damage after gamma irradiation. For donor dermis that is less sensitive to gamma irradiation damage, glycerol, sucrose or trehalose alone is able to provide good protection. However, for more sensitive donor dermis, only the glycerol and trehalose combination is able to provide sufficient tissue protection. CONCLUSION: Glycerol, sucrose and trehalose protects cryopreserved acellular human dermis against gamma irradiation damage. Cryopreservation solutions can be optimized to permit tissues for gamma sterilization to increase the safety human tissue implants.


Assuntos
Derme Acelular/efeitos dos fármacos , Crioprotetores/química , Raios gama/efeitos adversos , Glicerol/química , Sacarose/química , Trealose/química , Derme Acelular/efeitos da radiação , Criopreservação , Humanos
16.
Environ Sci Pollut Res Int ; 26(24): 24672-24682, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31240658

RESUMO

Intestinal mucositis is a common side effect during radiotherapy that could be largely prevented by compounds possessing anti-inflammatory or anti-oxidant properties, including extracts of propolis containing a high proportion of flavonoids. A specially formulated aqueous extract of propolis (PWE) has been prepared in such a way to preclude the inclusion of flavonoids but contain mostly organic aromatic acids to study whether it would still protect against radiation-induced intestinal mucositis and to study the possible involvement of apoptotic pathways. Rats were exposed to a gamma radiation dose of 8 Gy from a Cesium-137 source in order to inflict intestinal mucositis. Three days before exposure, rats were given PWE orally and treatment continued for 2 more days. Twenty-four hours later, rats were sacrificed, the small intestine was excised, and sections were examined histologically. Different parameters for apoptosis, inflammation, and oxidative stress were determined in the serum and in intestinal homogenates. Radiation exposure led to histological and biochemical signs of intestinal damage. This was associated with an increase in apoptotic indicators and derangement in oxidative stress parameters. All deranged parameters were largely prevented by PWE. The findings provide evidence that the protective effect of PWE against intestinal radiation damage involves not only its anti-inflammatory and anti-oxidant effects but also its anti-apoptotic properties as well.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Raios gama/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Própole/administração & dosagem , Animais , Inflamação , Mucosite , Ratos
17.
J Cancer Res Ther ; 15(3): 512-516, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169212

RESUMO

Introduction: Ionizing radiations produce free radicals which are often responsible for DNA damage or cell death. Grape seed extract (GSE) is a natural compound having an antioxidant that protects DNA, lipids, and proteins from free radical damages. In this study, radioprotective effect of the GSE has been investigated in mouse bone marrow cells using micronucleus test. Materials and Methods: Four groups of mice were investigated in this study: Mice in Group 1 were subjected to injection of distilled water with no irradiation. Mice in Group 2 were exposed to 3 Gy gamma radiation after the injection of distillated water. Mice in Group 3 were injected with 200 mg/kg of the GSE without any irradiation. In another group, mice were exposed to three gray gamma irradiation after the injection of GSE. Animals were killed, and slides were prepared from the bone marrow cells 24 h after irradiation. The slides were stained with May Grunwald-Giemsa method and analyzed microscopically. The frequency of the micronucleated polychromatic erythrocytes (MnPCEs), micronucleated normochromatic erythrocyte (MnNCEs), and polychromatic erythrocyte/polychromatic erythrocyte + normochromatic erythrocyte (PCE/PCE + NCE) ratios was calculated. Results: Injection of GSE significantly decreased the frequency of MnPCEs (P < 0.0001) and MnNCEs (P < 0.05) and increased the ratio of PCE/PCE + NCE (P < 0.0001) compared to the irradiated control group. Discussion and Conclusions: GSE could reduce clastogenic and cytotoxic effects of gamma irradiation in mice bone marrow cells; therefore, it can be concluded that the GSE is a herbal compound with radioprotective effects against gamma irradiation. Free radical scavenging and the antioxidant effects of the GSE probably are responsible mechanisms for the GSE radioprotective effects.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos da radiação , Raios gama , Extrato de Sementes de Uva/farmacologia , Protetores contra Radiação/farmacologia , Animais , Células da Medula Óssea/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/efeitos da radiação , Raios gama/efeitos adversos , Extrato de Sementes de Uva/química , Masculino , Camundongos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Testes para Micronúcleos , Protetores contra Radiação/química
18.
J Cancer Res Ther ; 15(3): 517-521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169213

RESUMO

Objective: Date palm seed extract (DPSE) has various compounds revealing antioxidant features. This study aimed to evaluate the radioprotective effect of DPSE in total body gamma irradiation. Materials and Methods: At first, chemical characteristics of DPSE were analyzed by ultraviolet, visible and Fourier transform infrared spectroscopy. Then, the toxicity of DPSE was assessed. For this purpose, 60 mice were divided into five groups, and each of the groups were injected by the doses of 100, 200, 300, 400, and 500 mg/kg, respectively. At the termination of the experiment, mortality rate and weight loss of all mice were evaluated over a period of 30 days. Finally, the radioprotective effect of DPSE was evaluated by dividing 36 mice into three groups: control, test, and placebo and then were irradiated by Cobalt-60. Results: According to the findings, there was no mortality due to DPSE. Furthermore, for the maximum dose of 500 mg/kg, the number of mice surviving at the termination of the experiment with and without injection of DPSE was reported as 83% and 41%, respectively. In addition, a significant difference was obtained between radiated mice with and without DPSE injection (P = 0.035). Conclusion: The findings showed that DPSE injected into mice before irradiation has no toxicity and could protect mice from lethal effects of total body irradiation. The use of DPSE as a new radioprotector agent in the human needs further studies, particularly clinical trials.


Assuntos
Raios gama , Phoeniceae/química , Extratos Vegetais/farmacologia , Protetores contra Radiação/farmacologia , Sementes/química , Animais , Raios gama/efeitos adversos , Masculino , Camundongos , Extratos Vegetais/química , Protetores contra Radiação/química , Análise Espectral , Taxa de Sobrevida , Irradiação Corporal Total
19.
J Pharmacol Sci ; 140(1): 79-85, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31178326

RESUMO

Bone marrow failure is a disease syndrome with the disability to produce mature blood cells. Pancytopenia is the most common manifestation of bone marrow failure. Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. The Sirt1 heterozygous and wild type mice were exposed to lethal 6.5 Gy 60Co-γ rays. The survival time and hematopoietic indexes were evaluated. The survival time of Sirt1 deficiency mice was significantly decreased. The numbers of platelets (PLT), reticulocytes (RET) and white blood cells (WBC) were significantly decreased. C57BL/6 mice were exposed to 6.5 Gy 60Co-γ rays then administrated with resveratrol (20 mg/kg/d) or vehicle. Resveratrol increased the survival time and protective against irradiation induced hematopoietic damage. Resveratrol also significantly increased the numbers of PLT, RET and WBC of mice. It also increased the hematopoietic area and karyocytes number. In HEK293T cells, the expression of LKB1 was significantly increased in cytoplasm but not in nuclei when treated with resveratrol (50 µM). These results suggest that Sirt1 deficiency might aggravate bone marrow failure. Resveratrol corrected this hematopoietic defect and LKB1 might involve in the protective effect on bone marrow failure.


Assuntos
Raios gama/efeitos adversos , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Pancitopenia/sangue , Pancitopenia/etiologia , Exposição à Radiação/efeitos adversos , Protetores contra Radiação/farmacologia , Resveratrol/farmacologia , Sirtuína 1/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Contagem de Leucócitos , Camundongos Knockout , Contagem de Plaquetas , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Contagem de Reticulócitos , Sirtuína 1/deficiência , Sirtuína 1/fisiologia , Estimulação Química
20.
Int J Oncol ; 54(6): 2117-2126, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081052

RESUMO

Transforming growth factor-ß1 (TGF-ß1) is a multifunctional cytokine that functions as a growth suppressor in normal epithelial cells and early stage tumors, but acts as a tumor promoter during malignant progression. However, the molecular basis underlying the conversion of TGF­ß1 function remains largely undefined. X­linked inhibitor of apoptosis­associated factor 1 (XAF1) is a pro­apoptotic tumor suppressor that frequently displays epigenetic inactivation in various types of human malignancies, including colorectal cancer. The present study explored whether the anti­apoptotic effect of TGF­ß1 is linked to its regulatory effect on XAF1 induction in human colon cancer cells under stressful conditions. The results revealed that TGF­ß1 treatment protected tumor cells from various apoptotic stresses, including 5­fluorouracil, etoposide and γ­irradiation. XAF1 expression was activated at the transcriptional level by these apoptotic stresses and TGF­ß1 blocked the stress­mediated activation of the XAF1 promoter. The study also demonstrated that mitogen­activated protein kinase kinase inhibition or extracellular signal­activated kinase (Erk)1/2 depletion induced XAF1 induction, while the activation of K­Ras (G12C) led to its reduction. In addition, TGF­ß1 blocked the stress­mediated XAF1 promoter activation and induction of apoptosis. This effect was abrogated if Erk1/2 was depleted, indicating that TGF­ß1 represses XAF1 transcription through Erk activation, thereby protecting tumor cells from apoptotic stresses. These findings point to a novel molecular mechanism underlying the tumor­promoting function of TGF­ß1, which may be utilized in the development of a novel therapeutic strategy for the treatment of colorectal cancer.


Assuntos
Neoplasias do Colo/metabolismo , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Neoplasias/genética , Fator de Crescimento Transformador beta1/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias do Colo/genética , Progressão da Doença , Etoposídeo/farmacologia , Fluoruracila/farmacologia , Raios gama/efeitos adversos , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas de Neoplasias/metabolismo , Regiões Promotoras Genéticas , Proteínas ras/metabolismo
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