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1.
J Radiat Res ; 62(2): 236-248, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33616187

RESUMO

The lung is sensitive to radiation and exhibits several phases of injury, with an initial phase of radiation-induced pneumonitis followed by delayed and irreversible fibrosis. The angiotensin-converting enzyme inhibitor captopril has been demonstrated to mitigate radiation lung injury and to improve survival in animal models of thoracic irradiation, but the mechanism remains poorly understood. Here we investigated the effect of captopril on early inflammatory events in the lung in female CBA/J mice exposed to thoracic X-ray irradiation of 17-17.9 Gy (0.5-0.745 Gy min-1). For whole-body + thoracic irradiation, mice were exposed to 7.5 Gy (0.6 Gy min-1) total-body 60Co irradiation and 9.5 Gy thoracic irradiation. Captopril was administered orally (110 mg kg-1 day-1) in the drinking water, initiated 4 h through to150 days post-irradiation. Captopril treatment increased survival from thoracic irradiation to 75% at 150 days compared with 0% survival in vehicle-treated animals. Survival was characterized by a significant decrease in radiation-induced pneumonitis and fibrosis. Investigation of early inflammatory events showed that captopril significantly attenuated macrophage accumulation and decreased the synthesis of radiation-induced interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines in the lungs of irradiated mice. Suppression of IL-1ß and TNF-α correlated with an increase of the anti-inflammatory cytokine IL-10 in the spleen with captopril treatment. We also found that captopril decreased markers for radiation-induced accelerated senescence in the lung tissue. Our data suggest that suppression of inflammation and senescence markers, combined with an increase of anti-inflammatory factors, are a part of the mechanism for captopril-induced survival in thoracic irradiated mice.


Assuntos
Envelhecimento/patologia , Captopril/uso terapêutico , Pneumonia/tratamento farmacológico , Tórax/efeitos da radiação , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Biomarcadores/metabolismo , Captopril/farmacologia , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/efeitos da radiação , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Macrófagos Alveolares/efeitos da radiação , Camundongos Endogâmicos CBA , Fibrose Pulmonar/patologia , Baço/efeitos dos fármacos , Baço/efeitos da radiação , Análise de Sobrevida , Irradiação Corporal Total , Raios X
2.
Toxicol Pathol ; 47(8): 1035-1037, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31645206

RESUMO

In the United States, the Food and Drug Administration (FDA) regulates the safe use of food ingredients, including food additives. Food additives are subject to FDA premarket review and approval, a process conducted by FDA scientists to evaluate the additive's safety for the intended conditions of use. Typically, an acceptable daily intake level is established by toxicologists based on the highest no observable adverse effect level for the most sensitive noncancer toxicity end point determined from a pivotal nonclinical study with application of an appropriate safety factor. Utilizing other information, including the additive's use and exposure levels, a safety determination (reasonable certainty of no harm) is made. During ongoing safety assessments, pathologists are often consulted by toxicologists for case-specific reasons, which may include verifying that an observed pathological effect is treatment related and adverse, confirming the determination of the pivotal study, endorsing a mode of action, or evaluating the human relevance of a toxicological effect found in experimental animals. Last year, the FDA took regulatory action to no longer allow the use of the food additive myrcene, a synthetic flavoring agent, based on results from National Toxicology Program carcinogenicity studies. The cancer and noncancer end points from the rat studies are discussed.


Assuntos
Monoterpenos Acíclicos/toxicidade , Alcenos/toxicidade , Qualidade de Produtos para o Consumidor , Aromatizantes/toxicidade , Aditivos Alimentares/toxicidade , Animais , Humanos , Nível de Efeito Adverso não Observado , Ratos , Medição de Risco , Testes de Toxicidade , Estados Unidos , United States Food and Drug Administration
3.
Toxicol Pathol ; 47(5): 645-648, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31117926

RESUMO

In histopathology, the presence of a tissue change that does not represent the tissue's normal appearance can often lead to an incorrect diagnosis and interpretation. These changes are collectively known as "artifacts" resulting from postmortem autolysis, improper fixation, problems with tissue handling or slide preparation procedures. Most tissue artifacts are obvious, yet some artifacts may be subtle, occur in relatively well-fixed tissue, and demand careful observation to avoid confusion with real biological lesions. The kidney often contains artifacts that may be observed throughout all regions of the renal parenchyma. Cortical tubule artifacts present the greatest challenge when discerning an artifact versus an induced lesion following exposure to a xenobiotic. However, confounding artifacts observed at the tip of the renal papilla may also be problematic for the pathologist. An uncommon artifact involving tinctorial alteration and rarefaction affecting the papillary tip of the rat kidney is described here and differentiated from treatment induced lesions of renal papillary necrosis.


Assuntos
Artefatos , Medula Renal/patologia , Animais , Medula Renal/efeitos dos fármacos , Necrose , Ratos , Xenobióticos/toxicidade
4.
Biol Sex Differ ; 9(1): 25, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907135

RESUMO

BACKGROUND: Doxorubicin (DOX), an anthracycline therapeutic, is widely used to treat a variety of cancer types and known to induce cardiomyopathy in a time and dose-dependent manner. Postmenopausal and hypertensive females are two high-risk groups for developing adverse effects following DOX treatment. This may suggest that endogenous reproductive hormones can in part suppress DOX-induced cardiotoxicity. Here, we investigated if the endogenous fluctuations in 17ß-estradiol (E2) and progesterone (P4) can in part suppress DOX-induced cardiomyopathy in SST-2 tumor-bearing spontaneously hypersensitive rats (SHRs) and evaluate if exogenous administration of E2 and P4 can suppress DOX-induced cardiotoxicity in tumor-bearing ovariectomized SHRs (ovaSHRs). METHODS: Vaginal cytology was performed on all animals to identify the stage of the estrous cycle. Estrous-staged SHRs received a single injection of saline, DOX, dexrazoxane (DRZ), or DOX combined with DRZ. OvaSHRs were implanted with time-releasing pellets that contained a carrier matrix (control), E2, P4, Tamoxifen (Tam), and combinations of E2 with P4 and Tam. Hormone pellet-implanted ovaSHRs received a single injection of saline or DOX. Cardiac troponin I (cTnI), E2, and P4 serum concentrations were measured before and after treatment in all animals. Cardiac damage and function were further assessed by echocardiography and histopathology. Weight, tumor size, and uterine width were measured for all animals. RESULTS: In SHRs, estrous-staged DOX treatment altered acute estrous cycling that ultimately resulted in prolonged diestrus. Twelve days after DOX administration, all SHRs had comparable endogenous circulating E2. Thirteen days after DOX treatment, SHRs treated during proestrus had decreased cardiac output and increased cTnI as compared to animals treated during estrus and diestrus. DOX-induced tumor reduction was not affected by estrous-staged treatments. In ovaSHRs, exogenous administration of E2 suppressed DOX-induced cardiotoxicity, while P4-implanted ovaSHRs were partly resistant. However, ovaSHRs treated with E2 and P4 did not have cardioprotection against DOX-induced damage. CONCLUSIONS: This study demonstrates that estrous-staged treatments can alter the extent of cardiac damage caused by DOX in female SHRs. The study also supports that exogenous E2 can suppress DOX-induced myocardial damage in ovaSHRs.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/prevenção & controle , Cardiotoxinas/efeitos adversos , Doxorrubicina/efeitos adversos , Estradiol/metabolismo , Estrogênios/metabolismo , Neoplasias/tratamento farmacológico , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Linhagem Celular Tumoral , Cronofarmacoterapia , Estro , Feminino , Humanos , Miocárdio/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Ovariectomia , Progesterona/fisiologia , Ratos Endogâmicos SHR , Troponina I/metabolismo
5.
Toxics ; 5(4)2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29051457

RESUMO

Hydrophobic sand is a relatively new method of urine collection in the rodent, comparable to the established method using a metabolic cage. Urine samples are often used in rodent research, especially for biomarkers of health changes after internal contamination from embedded metals, such as in a model of a military shrapnel wound. However, little research has been done on the potential interference of hydrophobic sand with urine metal concentrations either by contamination from the sand particulate, or adsorption of metals from the urine. We compare urine collected from rats using the metabolic cage method and the hydrophobic sand method for differences in metal concentration of common urinary metals, and examine physical properties of the sand material for potential sources of contamination. We found minimal risk of internal contamination of the rat by hydrophobic sand, and no interference of the sand with several common metals of interest (cobalt, strontium, copper, and manganese), although we advise caution in studies of aluminum in urine.

6.
J Radiat Res ; 58(5): 636-646, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28340212

RESUMO

Accidental high-dose radiation exposures can lead to multi-organ injuries, including radiation dermatitis. The types of cellular damage leading to radiation dermatitis are not completely understood. To identify the cellular mechanisms that underlie radiation-induced skin injury in vivo, we evaluated the time-course of cellular effects of radiation (14, 16 or 17 Gy X-rays; 0.5 Gy/min) in the skin of C57BL/6 mice. Irradiation of 14 Gy induced mild inflammation, observed histologically, but no visible hair loss or erythema. However, 16 or 17 Gy radiation induced dry desquamation, erythema and mild ulceration, detectable within 14 days post-irradiation. Histological evaluation revealed inflammation with mast cell infiltration within 14 days. Fibrosis occurred 80 days following 17 Gy irradiation, with collagen deposition, admixed with neutrophilic dermatitis, and necrotic debris. We found that in cultures of normal human keratinocytes, exposure to 17.9 Gy irradiation caused the upregulation of p21/waf1, a marker of senescence. Using western blot analysis of 17.9 Gy-irradiated mice skin samples, we also detected a marker of accelerated senescence (p21/waf1) 7 days post-irradiation, and a marker of cellular apoptosis (activated caspase-3) at 30 days, both preceding histological evidence of inflammatory infiltrates. Immunohistochemistry revealed reduced epithelial stem cells from hair follicles 14-30 days post-irradiation. Furthermore, p21/waf1 expression was increased in the region of the hair follicle stem cells at 14 days post 17 Gy irradiation. These data indicate that radiation induces accelerated cellular senescence in the region of the stem cell population of the skin.


Assuntos
Especificidade de Órgãos/efeitos da radiação , Lesões por Radiação/patologia , Envelhecimento da Pele/efeitos da radiação , Células-Tronco Adultas/efeitos da radiação , Envelhecimento , Animais , Apoptose/efeitos da radiação , Senescência Celular/efeitos da radiação , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Feminino , Fibrose , Folículo Piloso/patologia , Folículo Piloso/efeitos da radiação , Queratinócitos/patologia , Queratinócitos/efeitos da radiação , Camundongos Endogâmicos C57BL , Pele/patologia , Pele/efeitos da radiação , Úlcera/patologia
7.
Cancer Chemother Pharmacol ; 76(3): 447-59, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26108538

RESUMO

PURPOSE: Chemotherapy with doxorubicin (Dox) causes dose-limiting cardiotoxicity. We investigated the role that gender has on cardiosensitivity to Dox treatment by evaluating reproductive hormone levels in male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs) and expression of mitochondria-related genes in male and female adult SHRs. METHODS: SST-2 breast tumor-bearing SHRs were treated with saline, Dox, dexrazoxane (Drz) or both Dox and Drz and monitored for 14 days. Tumor size was used to monitor anticancer activity. Heart weight, cardiac lesion score and serum levels of cardiac troponin T (cTnT) were used to determine cardiotoxicity. Serum estradiol (E2) and testosterone were evaluated using electrochemiluminescence immunoassays. Expression of mitochondria-related genes was profiled in heart by MitoChip array analyses. RESULTS: Dox significantly reduced tumor volume (±Drz) and increased heart weight in all genders (13-30% vs. control). Higher heart lesion scores were observed in reproductively normal animals (male 2.9, female 2.2) than in hormone-deficient animals (c-male 1.7, o-female 1.9). Lesion score and cTnT inversely correlated with hormone levels. Reduced levels of both sex hormones were observed after Dox treatment. Gene expression analyses of Dox-treated hearts showed significant differential expression of oxidative stress genes in male hearts and apoptotic genes in both male and female hearts. CONCLUSIONS: Our results demonstrate that adult tumor-bearing male SHRs are more cardiosensitive to Dox than female or hormone-deficient animals. We provide evidence to suggest that reproductive hormones negatively regulate or are inhibited by Dox-induced cardiotoxicity and the selective cytotoxic mechanism likely functions through the greater activation of oxidative stress and apoptosis in male SHRs.


Assuntos
Doxorrubicina/farmacologia , Hormônios Esteroides Gonadais/metabolismo , Cardiopatias/metabolismo , Hipertensão/metabolismo , Mitocôndrias/genética , Animais , Apoptose/fisiologia , Doxorrubicina/toxicidade , Feminino , Expressão Gênica/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Hipertensão/induzido quimicamente , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Animais , Estresse Oxidativo/genética , Ratos , Ratos Endogâmicos SHR , Fatores Sexuais
8.
Toxics ; 3(4): 499-514, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-29051474

RESUMO

Tungsten-based composites have been recommended as a suitable replacement for depleted uranium. Unfortunately, one of these mixtures composed of tungsten (W), nickel (Ni) and cobalt (Co) induced rhabdomyosarcomas when implanted into the leg muscle of laboratory rats and mice to simulate a shrapnel wound. The question arose as to whether the neoplastic effect of the mixture could be solely attributed to one or more of the metal components. To investigate this possibility, pellets with one or two of the component metals replaced with an identical amount of the biologically-inert metal tantalum (Ta) were manufactured and implanted into the quadriceps of B6C3F1 mice. The mice were followed for two years to assess potential adverse health effects. Implantation with WTa, CoTa or WNiTa resulted in decreased survival, but not to the level reported for WNiCo. Sarcomas in the implanted muscle were found in 20% of the CoTa-implanted mice and 5% of the WTa- and WCoTa-implanted rats and mice, far below the 80% reported for WNiCo-implanted mice. The data obtained from this study suggested that no single metal is solely responsible for the neoplastic effects of WNiCo and that a synergistic effect of the three metals in tumor development was likely.

9.
Int J Toxicol ; 34(1): 44-54, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25544565

RESUMO

Continued improvements in the ballistic properties of military munitions have led to metal formulations for which little are known about the long-term health effects. Previously we have shown that a military-grade tungsten alloy comprised of tungsten, nickel, and cobalt, when embedded into the leg muscle of F344 rats to simulate a fragment wound, induces highly aggressive metastatic rhabdomyosarcomas. An important follow-up when assessing a compound's carcinogenic potential is to test it in a second rodent species. In this study, we assessed the health effects of embedded fragments of 2 military-grade tungsten alloys, tungsten/nickel/cobalt and tungsten/nickel/iron, in the B6C3F1 mouse. Implantation of tungsten/nickel/cobalt pellets into the quadriceps muscle resulted in the formation of a rhabdomyosarcoma around the pellet. Conversely, implantation of tungsten/nickel/iron did not result in tumor formation. Unlike what was seen in the rat model, the tumors induced by the tungsten/nickel/cobalt did not exhibit aggressive growth patterns and did not metastasize.


Assuntos
Ligas/toxicidade , Corpos Estranhos , Metais Pesados/toxicidade , Neoplasias Musculares/induzido quimicamente , Músculo Esquelético/efeitos dos fármacos , Rabdomiossarcoma/induzido quimicamente , Ligas/farmacocinética , Animais , Masculino , Metais Pesados/farmacocinética , Metais Pesados/urina , Camundongos , Neoplasias Musculares/metabolismo , Neoplasias Musculares/patologia , Músculo Esquelético/patologia , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Distribuição Tecidual , Armas
10.
Toxicol Pathol ; 43(5): 662-74, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25520306

RESUMO

Attempts to characterize and formally qualify biomarkers for regulatory purposes have raised questions about how histological and histopathological methods impact the evaluation of biomarker performance. A group of pathologists was asked to analyze digitized images prepared from rodent kidney injury experiments in studies designed to investigate sources of variability in histopathology evaluations. Study A maximized variability by using samples from diverse studies and providing minimal guidance, contextual information, or opportunities for pathologist interaction. Study B was designed to limit interpathologist variability by using more uniform image sets from different locations within the same kidneys and allowing pathologist selected interactions to discuss and identify the location and injury to be evaluated but without providing a lexicon or peer review. Results from this study suggest that differences between pathologists and across models of disease are the largest sources of variability in evaluations and that blind evaluations do not generally make a significant difference. Results of this study generally align with recommendations from both industry and the U.S. Food and Drug Administration and should inform future studies examining the effects of common lexicons and scoring criteria, peer review, and blind evaluations in the context of biomarker performance assessment.


Assuntos
Moléculas de Adesão Celular/urina , Nefropatias/patologia , Nefropatias/urina , Animais , Biomarcadores/urina , Cisplatino/toxicidade , Nefropatias/induzido quimicamente , Masculino , Curva ROC , Ratos , Ratos Sprague-Dawley
11.
PLoS One ; 8(8): e70575, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23940596

RESUMO

Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress-mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-α) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito-Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of mitochondrially-directed agents to mitigate oxidative stress-induced cardiotoxicity. Our findings also emphasize the novel role of specific protein oxidation markers and autophagic mechanisms for cardioprotection.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Dexrazoxano/uso terapêutico , Compostos Organofosforados/uso terapêutico , Piperidinas/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Oxirredução/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR
12.
Int J Radiat Oncol Biol Phys ; 79(2): 571-8, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20950962

RESUMO

PURPOSE: A class of naturally occurring isoforms of tocopherol (tocols) was shown to have varying degrees of protection when administered before radiation exposure. We recently demonstrated that α-tocopherol succinate (TS) is a potential radiation prophylactic agent. Our objective in this study was to further investigate the mechanism of action of TS in mice exposed to (60)Co γ-radiation. METHODS AND MATERIALS: We evaluated the effects of TS on expression of antioxidant enzymes and oncogenes by quantitative RT-PCR in bone marrow cells of (60)Co γ-irradiated mice. Further, we tested the ability of TS to rescue and repopulate hematopoietic stem cells by analyzing bone marrow cellularity and spleen colony forming unit in spleen of TS-injected and irradiated mice. RESULTS: Our results demonstrate that TS modulated the expression of antioxidant enzymes and inhibited expression of oncogenes in irradiated mice at different time points. TS also increased colony forming unit-spleen numbers and bone marrow cellularity in irradiated mice. CONCLUSIONS: Results provide additional support for the observed radioprotective efficacy of TS and insight into mechanisms.


Assuntos
Antioxidantes/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Protetores contra Radiação/farmacologia , alfa-Tocoferol/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos da radiação , Radioisótopos de Cobalto/farmacologia , Ensaio de Unidades Formadoras de Colônias/métodos , Primers do DNA/genética , Genes jun/efeitos dos fármacos , Genes jun/efeitos da radiação , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Glutationa Redutase/efeitos dos fármacos , Glutationa Redutase/metabolismo , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/fisiologia , Células-Tronco Hematopoéticas/efeitos da radiação , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/efeitos da radiação , Esterno/citologia , Esterno/efeitos dos fármacos , Esterno/efeitos da radiação , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo
13.
Haematologica ; 95(12): 1996-2004, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20823133

RESUMO

BACKGROUND: Exposure to γ-radiation causes rapid hematopoietic cell apoptosis and bone marrow suppression. However, there are no approved radiation countermeasures for the acute radiation syndrome. In this study, we demonstrated that natural δ-tocotrienol, one of the isomers of vitamin E, significantly enhanced survival in total body lethally irradiated mice. We explored the effects and mechanisms of δ-tocotrienol on hematopoietic progenitor cell survival after γ-irradiation in both in vivo and in vitro experiments. DESIGN AND METHODS: CD2F1 mice and human hematopoietic progenitor CD34(+) cells were treated with δ-tocotrienol or vehicle control 24 h before or 6 h after γ-irradiation. Effects of δ-tocotrienol on hematopoietic progenitor cell survival and regeneration were evaluated by clonogenicity studies, flow cytometry, and bone marrow histochemical staining. δ-tocotrienol and γ-irradiation-induced signal regulatory activities were assessed by immunofluorescence staining, immunoblotting and short-interfering RNA assay. RESULTS: δ-tocotrienol displayed significant radioprotective effects. A single injection of δ-tocotrienol protected 100% of CD2F1 mice from total body irradiation-induced death as measured by 30-day post-irradiation survival. δ-tocotrienol increased cell survival, and regeneration of hematopoietic microfoci and lineage(-)/Sca-1(+)/ckit(+) stem and progenitor cells in irradiated mouse bone marrow, and protected human CD34(+) cells from radiation-induced damage. δ-tocotrienol activated extracellular signal-related kinase 1/2 phosphorylation and significantly inhibited formation of DNA-damage marker γ-H2AX foci. In addition, δ-tocotrienol up-regulated mammalian target of rapamycin and phosphorylation of its downstream effector 4EBP-1. These alterations were associated with activation of mRNA translation regulator eIF4E and ribosomal protein S6, which is responsible for cell survival and growth. Inhibition of extracellular signal-related kinase 1/2 expression by short interfering RNA abrogated δ-tocotrienol-induced mammalian target of rapamycin phosphorylation and clonogenicity, and increased γ-H2AX foci formation in irradiated CD34(+) cells. CONCLUSIONS: Our data indicate that δ-tocotrienol protects mouse bone marrow and human CD34(+) cells from radiation-induced damage through extracellular signal-related kinase activation-associated mammalian target of rapamycin survival pathways.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Vitamina E/análogos & derivados , Animais , Antígenos CD34/metabolismo , Western Blotting , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Relação Dose-Resposta à Radiação , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Fator de Iniciação 4E em Eucariotos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , Raios gama , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos da radiação , Histonas/metabolismo , Humanos , Masculino , Camundongos , Microscopia de Fluorescência , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Interferência de RNA , Proteína S6 Ribossômica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Análise de Sobrevida , Serina-Treonina Quinases TOR/genética , Vitamina E/farmacologia
14.
Radiat Res ; 173(6): 738-47, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20518653

RESUMO

We analyzed the radioprotective effects of gamma-tocotrienol (GT3) on hematopoietic stem cells (HSCs) and progenitor cells (HPCs) in sublethally irradiated mice. Flow cytometry analysis indicated that radiation depleted HPCs (c-Kit(+), Lin(-)) to 40% at days 2 and 4 after total-body irradiation (TBI) in all treatment groups. The HPC numbers in GT3-treated mice recovered almost completely (90%) at day 7 but remained depleted in vehicle-treated mice (30%) even at day 13 after TBI. An in vitro colony-forming assay on sorted HSCs (Lin(-), Sca1(+), c-Kit(+)) indicated that TBI reduced the number of colonies to 40% and 50% at day 17 and 60, respectively, in vehicle-treated groups compared to unirradiated controls (naïve). GT3-treated irradiated mice maintained higher numbers of colonies (86% and 80% compared to naïve mice), thereby preserving the self-renewable capacity of HSCs. Histopathology of sternal bone marrow indicated more regenerative microfoci for myeloid cells and megakaryocytes and higher overall cellularity in GT3-treated mice compared to vehicle controls at days 7 and 13 after TBI. GT3 treatment also reduced the frequency of micronucleated erythrocytes significantly in irradiated mice. Our results demonstrate that GT3 protected hematopoietic tissue by preserving the HSCs and HPCs and by preventing persistent DNA damage.


Assuntos
Cromanos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Protetores contra Radiação/farmacologia , Vitamina E/análogos & derivados , Irradiação Corporal Total , Animais , Dano ao DNA , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Eritrócitos/patologia , Eritrócitos/efeitos da radiação , Citometria de Fluxo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Masculino , Camundongos , Testes para Micronúcleos , Vitamina E/farmacologia
15.
J Inherit Metab Dis ; 33(3): 195-210, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20464498

RESUMO

Genetic mutations that severely diminish the activity of aspartoacylase (ASPA) result in the fatal brain dysmyelinating disorder, Canavan disease. There is no effective treatment. ASPA produces free acetate from the concentrated brain metabolite, N-acetylaspartate (NAA). Because acetyl coenzyme A is a key building block for lipid synthesis, we postulated that the inability to catabolize NAA leads to a brain acetate deficiency during a critical period of CNS development, impairing myelination and possibly other aspects of brain development. We tested the hypothesis that acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of Canavan disease. Glyceryltriacetate (GTA) was administered orally to tremor rats starting 7 days after birth, and was continued in food and water after weaning. Motor function, myelin lipids, and brain vacuolation were analyzed in GTA-treated and untreated tremor rats. Significant improvements were observed in motor performance and myelin galactocerebroside content in tremor rats treated with GTA. Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance. We also examined the expression of the acetyl coenzyme A synthesizing enzyme acetyl coenzyme A synthase 1 and found upregulation of expression in tremor rats, with a return to near normal expression levels in GTA-treated tremor rats. These results confirm the critical role played by NAA-derived acetate in brain myelination and development, and demonstrate the potential usefulness of acetate therapy for the treatment of Canavan disease.


Assuntos
Acetatos/uso terapêutico , Ácido Aspártico/análogos & derivados , Doença de Canavan/terapia , Mutação , Animais , Ácido Aspártico/metabolismo , Ácido Aspártico/uso terapêutico , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Heterozigoto , Lipídeos/química , Masculino , Bainha de Mielina/química , Fenótipo , Ratos , Resultado do Tratamento
16.
Radiat Res ; 173(3): 319-32, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20199217

RESUMO

Abstract Although it is documented that concurrent wounding increases mortality from radiation injury, the molecular mechanism of combined injury is unknown. In this study, mice were exposed to gamma radiation followed by skin wounding. Wound trauma exacerbated radiation-induced mortality, reducing the LD(50/30) from 9.65 Gy to 8.95 Gy. Analyses of histopathology, inducible nitric oxide synthase (iNOS), and serum cytokines were performed on mouse ileum and skin at various times after 9.75 Gy and/or wounding. In the ileum, the villi were significantly shortened 3 days postirradiation but not after wounding; combined injury resulted in decreased villus width and tunica muscularis thickness. The skin of mice subjected to combined injury was less cellular and had a smaller healing bud than the skin of mice subjected to wounding alone. Combined injury significantly delayed wound closure times; it also prolonged the increased levels of iNOS protein in the skin and ileum. iNOS up-regulation was correlated with increases in transcription factors, including NF-kappaB and NF-IL6. The increase in NF-IL6 may be due to increases in cytokines, including IL-1beta, -6, -8, -9, -10 and -13, G-CSF, eotaxin, INF-gamma, MCP-1, MIP-1alpha and MIP-1beta. Combined injury resulted in early detection of bacteria in the blood of the heart and liver, whereas radiation alone resulted in later detection of bacteria; only a transient bacteremia occurred after wounding alone. Results suggest that enhancement of iNOS, cytokines and bacterial infection triggered by combined injury may contribute to mortality. Agents that inhibit these responses may prove to be therapeutic for combined injury and may reduce related mortality.


Assuntos
Infecções Bacterianas , Citocinas/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/microbiologia , Transdução de Sinais/efeitos da radiação , Animais , Peso Corporal/efeitos da radiação , Citocinas/sangue , Ingestão de Líquidos/efeitos da radiação , Indução Enzimática/efeitos da radiação , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos da radiação , Coração/microbiologia , Coração/efeitos da radiação , Íleo/metabolismo , Íleo/efeitos da radiação , Interleucina-6/metabolismo , Fígado/microbiologia , Fígado/efeitos da radiação , Camundongos , Mortalidade , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Pele/lesões , Pele/metabolismo , Pele/fisiopatologia , Pele/efeitos da radiação , Fatores de Tempo , Cicatrização/efeitos da radiação
17.
Exp Hematol ; 38(4): 270-81, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20116413

RESUMO

OBJECTIVE: Angiotensin II (Ang II), a potent vasoconstrictor, affects the growth and development of hematopoietic cells. Mixed findings have been reported for the effects of angiotensin-converting enzyme (ACE) inhibitors on radiation-induced injury to the hematopoietic system. We investigated the consequences of different regimens of the ACE inhibitor captopril on radiation-induced hematopoietic injury. MATERIALS AND METHODS: C57BL/6 mice were either sham-irradiated or exposed to (60)Co total body irradiation (0.6 Gy/min). Captopril was provided in the water for different time periods relative to irradiation. RESULTS: In untreated mice, the survival rate from 7.5 Gy was 50% at 30 days postirradiation. Captopril treatment for 7 days prior to irradiation resulted in radiosensitization with 100% lethality and a rapid decline in mature blood cells. In contrast, captopril treatment beginning 1 hour postirradiation and continuing for 30 days resulted in 100% survival, with improved recovery of mature blood cells and multilineage hematopoietic progenitors. In nonirradiated control mice, captopril biphasically modulated Lin(-) marrow progenitor cell cycling. After 2 days, captopril suppressed G(0)-G(1) transition and a greater number of cells entered a quiescent state. However, after 7 days of captopril treatment Lin(-) progenitor cell cycling increased compared to untreated control mice. CONCLUSION: These findings suggest that ACE inhibition affects hematopoietic recovery following radiation by modulating the hematopoietic progenitor cell cycle. The timing of captopril treatment relative to radiation exposure differentially affects the viability and repopulation capacity of spared hematopoietic stem cells and, therefore, can result in either radiation protection or radiation sensitization.


Assuntos
Captopril/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Proteção Radiológica/métodos , Irradiação Corporal Total , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Captopril/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Fatores de Tempo
18.
J Trauma ; 67(4): 848-55, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19820595

RESUMO

BACKGROUND: Major improvements have been made in the development of novel dressings with hemostatic properties to control heavy bleeding in noncompressible areas. To test the relative efficacy of different formulations in bleeding control, recently manufactured products need to be compared using a severe injury model. METHODS: Ten hemostatic dressings and the standard gauze bandage were tested in anesthetized Yorkshire pigs hemorrhaged by full transection of the femoral vasculature at the level of the groin. Application of these dressings with a 5-minute compression period (at approximately 200 mm Hg) was followed with a subsequent infusion of colloid for a period of 30 minutes. Primary outcomes were survival and amount and incidence of bleeding after dressing application. Vital signs and wound temperature were continuously recorded throughout the 3-hour experimental observation. RESULTS: These findings indicated that four dressings were effective in improving bleeding control and superior to the standard gauze bandage. This also correlated with increased survival rates. Absorbent property, flexibility, and the hemostatic agent itself were identified as the critical factors in controlling bleeding on a noncompressible transected vascular and tissue injury. CONCLUSIONS: Celox, QuikClot ACS, WoundStat, and X-Sponge ranked superior in terms of low incidence of rebleeding, volume of blood loss, maintenance of mean arterial pressure >40 mm Hg, and survival.


Assuntos
Bandagens , Técnicas Hemostáticas/instrumentação , Absorção , Animais , Biopolímeros/uso terapêutico , Desenho de Equipamento , Virilha/lesões , Teste de Materiais , Choque Hemorrágico/prevenção & controle , Suínos
19.
Gastroenterology ; 137(4): 1367-79.e1-6, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19622359

RESUMO

BACKGROUND & AIMS: Gastric cancer results from a combination of Helicobacter pylori (H pylori) infection, exposure to dietary carcinogens, and predisposing genetic make-up. Because the role of these factors in gastric carcinogenesis cannot be determined readily in human beings, the present study examined the role of an oral carcinogen and H pylori infection in rhesus monkeys. METHODS: Gastroscopies were performed in 23 monkeys assigned to 4 groups: controls; nitrosating carcinogen ethyl-nitro-nitrosoguanidine administration alone; inoculation of a virulent H pylori strain alone (H); and ethyl-nitro-nitrosoguanidine in combination with H pylori (EH). Follow-up gastroscopies and biopsies were performed at 3-month intervals for 5 years for pathologic and molecular studies. RESULTS: Postinoculation, H and EH groups showed persistent infection and antral gastritis. Starting at 2 and 5 years, respectively, gastric intestinal metaplasia and intraepithelial neoplasia developed in 3 EH monkeys but in no other groups. Transcriptional analysis of biopsy specimens at 5 years revealed group-specific expression profiles, with striking changes in EH monkeys, plus a neoplasia-specific expression profile characterized by changes in multiple cancer-associated genes. Importantly, this neoplastic profile was evident in nonneoplastic mucosa, suggesting that the identified genes may represent markers preceding cancer. CONCLUSIONS: Gastric intraglandular neoplasia is induced in primates when H pylori infection is associated with consumption of a carcinogen similar to the nitrosamines found in pickled vegetables, suggesting that H pylori and the carcinogen synergistically induce gastric neoplasia in primates.


Assuntos
Carcinógenos/toxicidade , Dieta/efeitos adversos , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Metilnitronitrosoguanidina/análogos & derivados , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/microbiologia , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/microbiologia , Animais , Biópsia , Carcinoma in Situ/induzido quimicamente , Carcinoma in Situ/genética , Carcinoma in Situ/microbiologia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Análise por Conglomerados , Reparo do DNA , Modelos Animais de Doenças , Progressão da Doença , Feminino , Gastrite/induzido quimicamente , Gastrite/genética , Gastrite/microbiologia , Gastroscopia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Infecções por Helicobacter/patologia , Macaca mulatta , Masculino , Metaplasia , Metilnitronitrosoguanidina/toxicidade , Análise de Sequência com Séries de Oligonucleotídeos , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Fatores de Tempo
20.
J Radiat Res ; 49(4): 361-72, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18434686

RESUMO

The effects of genistein on 30-day survival and delayed lung injury were examined in C57BL/6J female mice. A single subcutaneous injection of vehicle (PEG-400) or genistein (200 mg/kg) was administered 24 h before total body irradiation (7.75 Gy (60)Co, 0.6 Gy/min). Experimental groups were: No treatment + Sham (NC), Vehicle + Sham (VC), Genistein + Sham (GC), Radiation only (NR), Vehicle + Radiation (VR), Genistein + Radiation (GR). Thirty-day survivals after 7.75 Gy were: NR 23%, VR 53%, and GR 92%, indicating significant protection from acute radiation injury by genistein. Genistein also mitigated radiation-induced weight loss on days 13-28 postirradiation. First generation lung fibroblasts were analyzed for micronuclei 24 h postirradiation. Fibroblasts from the lungs of GR-treated mice had significantly reduced micronuclei compared with NR mice. Collagen deposition was examined by histochemical staining. At 90 days postirradiation one half of the untreated and vehicle irradiated mice had focal distributions of small collagen-rich plaques in the lungs, whereas all of the genistein-treated animals had morphologically normal lungs. Radiation reduced the expression of COX-2, transforming growth factor-beta receptor (TGFbetaR) I and II at 90 days after irradiation. Genistein prevented the reduction in TGFbetaRI. However, by 180 days postirradiation, these proteins normalized in all groups. These results demonstrate that genistein protects against acute radiation-induced mortality in female mice and that GR-treated mice have reduced lung damage compared to NR or VR. These data suggest that genistein is protective against a range of radiation injuries.


Assuntos
Citocinas/análise , Genisteína/administração & dosagem , Lesões por Radiação/metabolismo , Lesões por Radiação/prevenção & controle , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/prevenção & controle , Irradiação Corporal Total , Animais , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Feminino , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Doses de Radiação , Protetores contra Radiação/administração & dosagem , Análise de Sobrevida , Taxa de Sobrevida
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